bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from Phosphatidylserine-Targeting Antibody Induces M1 Macrophage Polarization and Promotes Myeloid-Derived Suppressor Cell Differentiation
Authors: Yin Yi , Huang Xianming , Lynn Kristi D. , Thorpe Philip E.
Published: March 2024

Abstract
Multiple tumor-derived factors are responsible for the accumulation and expansion of immune-suppressing myeloid-derived suppressor cells (MDSC) and M2-like tumor-associated macrophages (TAM) in tumors. Here, we show that treatment of tumor-bearing mice with docetaxel in combination with the phosphatidylserine-targeting antibody 2aG4 potently suppressed the growth and progression of prostate tumors, depleted M2-like TAMs, and MDSCs, and increased the presence of M1-like TAMs and mature dendritic cells in the tumors. In addition, the antibody markedly altered the cytokine balance in the tumor microenvironment from immunosuppressive to immunostimulatory. In vitro studies confirmed that 2aG4 repolarized TAMs from an M2- to an M1-like phenotype and drove the differentiation of MDSCs into M1-like TAMs and functional dendritic cells. These data suggest that phosphatidylserine is responsible for the expansion of MDSCs and M2-like TAMs in tumors, and that bavituximab, a phosphatidylserine-targeting antibody currently in clinical trials for cancer, could reverse this process and reactivate antitumor immunity. Cancer Immunol Res; 1(4); 256–68. ©2013 AACR.
Data from CD4 T Cells Require ICOS-Mediated PI3K Signaling to Increase T-Bet Expression in the Setting of Anti-CTLA-4 Therapy
Authors: Chen Hong , Fu Tihui , Suh Woong-Kyung , Tsavachidou Dimitra , Wen Sijin , Gao Jianjun , Ng Tang Derek , He Qiuming , Sun Jingjing , Sharma Padmanee
Published: March 2024

Abstract
The transcription factor T-bet controls the Th1 genetic program in T cells for effective antitumor responses. Anti-CTLA-4 immunotherapy elicits dramatic antitumor responses in mice and in human patients; however, factors that regulate T-bet expression during an antitumor response mediated by anti-CTLA-4 remain to be elucidated. We were the first to report that treatment with anti-CTLA-4 led to an increase in the frequency of T cells expressing inducible costimulator (ICOS). In both treated patients and mice, our data revealed that CD4+ICOShi T cells can act as effector T cells, which produce the Th1 cytokine IFN-γ. We also showed in a small retrospective analysis that an increased frequency of CD4+ICOShi T cells correlated with better clinical outcome and the absence of ICOS or its ligand (ICOSL) in mouse models led to impaired tumor rejection. Here, we show that CD4+ICOShi T cells from anti-CTLA-4–treated patients had an increase in signaling via the phospoinositide-3-kinase (PI3K) pathway and an increase in expression of T-bet. An ICOS-specific siRNA transfected into human T cells led to diminished PI3K signaling and T-bet expression. Therefore, we hypothesized that ICOS, and specifically ICOS-mediated PI3K signaling, was required for T-bet expression. We conducted studies in ICOS-deficient and ICOS-YF mice, which have a single amino acid change that abrogates PI3K signaling by ICOS. We found that ICOS-mediated PI3K signaling is required for T-bet expression during an antitumor response elicited by anti-CTLA-4 therapy. Our data provide new insight into the regulation of T-bet expression and suggest that ICOS can be targeted to improve Th1 antitumor responses. Cancer Immunol Res; 2(2); 167–76. ©2013 AACR.
Data from PARP1 Suppresses the Transcription of PD-L1 by Poly(ADP-Ribosyl)ating STAT3
Authors: Ding Ling , Chen Xi , Xu Xiaqing , Qian Yuli , Liang Guikai , Yao Fengqi , Yao Zhangting , Wu Honghai , Zhang Jieqiong , He Qiaojun , Yang Bo
Published: March 2024

Abstract
Studies have pointed to a role of PARP1 in regulating gene expression through poly(ADP-ribosyl)ating, sequence-specific, DNA-binding transcription factors. However, few examples exist that link this role of PARP1 to the immunogenicity of cancer cells. Here, we report that PARP1 poly(ADP-ribosyl)ates STAT3 and subsequently promotes STAT3 dephosphorylation, resulting in reduced transcriptional activity of STAT3 and expression of PD-L1. In this study, we showed that PARP1 silencing or pharmacologic inhibition enhanced the transcription of PD-L1 in cancer cells, which was accompanied by the upregulation of PD-L1 protein expression, both in the cytoplasm and on the cell surface. This induction of PD-L1 was attenuated in the absence of the transcription factor STAT3. Cell-based studies indicated that PARP1 interacted directly with STAT3 and caused STAT3 poly(ADP-ribosyl)ation. STAT3′s activation of PD-L1 transcription was abolished by the overexpression of wild-type PARP1 but not mutant PARP1, which lacks catalytic activity. PARP1 downregulation or catalytic inhibition enhanced the phosphorylation of STAT3, which was reversed by the ectopic expression of wild-type PARP1 but not by mutated PARP1. An inverse correlation between PARP1 and PD-L1 was also observed in clinical ovarian cancer samples. Overall, our study revealed PARP1-mediated poly(ADP-ribosyl)ation of STAT3 as a key step in inhibiting the transcription of PD-L1, and this mechanism exists in a variety of cancer cells.
Data from Antigen-Specific Bacterial Vaccine Combined with Anti-PD-L1 Rescues Dysfunctional Endogenous T Cells to Reject Long-Established Cancer
Authors: Binder David C. , Engels Boris , Arina Ainhoa , Yu Ping , Slauch James M. , Fu Yang-Xin , Karrison Theodore , Burnette Byron , Idel Christian , Zhao Ming , Hoffman Robert M. , Munn David H. , Rowley Donald A. , Schreiber Hans
Published: March 2024

Abstract
Immunogenic tumors grow progressively even when heavily infiltrated by CD8+ T cells. We investigated how to rescue CD8+ T-cell function in long-established immunogenic melanomas that contained a high percentage of endogenous PD-1+ tumor-specific CD8+ T cells that were dysfunctional. Treatment with αPD-L1– and αCTLA-4–blocking antibodies did not prevent tumors from progressing rapidly. We then tested exogenous tumor-specific antigen delivery into tumors using Salmonella Typhimurium A1-R (A1-R) to increase antigen levels and generate a proinflammatory tumor microenvironment. Antigen-producing A1-R rescued the endogenous tumor-specific CD8+ T-cell response: Proliferation was induced in the lymphoid organs and effector function was recovered in the tumor. Treatment with antigen-producing A1-R led to improved mouse survival and resulted in 32% rejection of long-established immunogenic melanomas. Following treatment with antigen-producing A1-R, the majority of tumor-specific CD8+ T cells still expressed a high level of PD-1 in the tumor. Combining antigen-producing A1-R with αPD-L1-blocking antibody enhanced the expansion of tumor-specific CD8+ T cells and resulted in 80% tumor rejection. Collectively, these data show a powerful new therapeutic approach to rescue dysfunctional endogenous tumor-specific CD8+ T cells and eradicate advanced immunogenic tumors. Cancer Immunol Res; 1(2); 123–33. ©2013 AACR.
Data from Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures
Authors: Zeng Dongqiang , Li Meiyi , Zhou Rui , Zhang Jingwen , Sun Huiying , Shi Min , Bin Jianping , Liao Yulin , Rao Jinjun , Liao Wangjun
Published: March 2024

Abstract
Tumor microenvironment (TME) cells constitute a vital element of tumor tissue. Increasing evidence has elucidated their clinicopathologic significance in predicting outcomes and therapeutic efficacy. Nonetheless, no studies have reported a systematic analysis of cellular interactions in the TME. In this study, we comprehensively estimated the TME infiltration patterns of 1,524 gastric cancer patients and systematically correlated the TME phenotypes with genomic characteristics and clinicopathologic features of gastric cancer using two proposed computational algorithms. Three TME phenotypes were defined, and the TMEscore was constructed using principal component analysis algorithms. The high TMEscore subtype was characterized by immune activation and response to virus and IFNγ. Activation of transforming growth factor β, epithelial–mesenchymal transition, and angiogenesis pathways were observed in the low TMEscore subtype, which are considered T-cell suppressive and may be responsible for significantly worse prognosis in gastric cancer [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.33–0.54; P < 0.001]. Multivariate analysis revealed that the TMEscore was an independent prognostic biomarker, and its value in predicting immunotherapeutic outcomes was also confirmed (IMvigor210 cohort: HR, 0.63; 95% CI, 0.46–0.89; P = 0.008; GSE78220 cohort: HR, 0.25; 95% CI, 0.07–0.89; P = 0.021). Depicting a comprehensive landscape of the TME characteristics of gastric cancer may, therefore, help to interpret the responses of gastric tumors to immunotherapies and provide new strategies for the treatment of cancers.
Data from PD-L1 Expression in Triple-Negative Breast Cancer
Authors: Mittendorf Elizabeth A. , Philips Anne V. , Meric-Bernstam Funda , Qiao Na , Wu Yun , Harrington Susan , Su Xiaoping , Wang Ying , Gonzalez-Angulo Ana M. , Akcakanat Argun , Chawla Akhil , Curran Michael , Hwu Patrick , Sharma Padmanee , Litton Jennifer K. , Molldrem Jeffrey J. , Alatrash Gheath
Published: March 2024

Abstract
Early-phase trials targeting the T-cell inhibitory molecule programmed cell death ligand 1 (PD-L1) have shown clinical efficacy in cancer. This study was undertaken to determine whether PD-L1 is overexpressed in triple-negative breast cancer (TNBC) and to investigate the loss of PTEN as a mechanism of PD-L1 regulation. The Cancer Genome Atlas (TCGA) RNA sequencing data showed significantly greater expression of the PD-L1 gene in TNBC (n = 120) compared with non-TNBC (n = 716; P < 0.001). Breast tumor tissue microarrays were evaluated for PD-L1 expression, which was present in 19% (20 of 105) of TNBC specimens. PD-L1+ tumors had greater CD8+ T-cell infiltrate than PD-L1− tumors (688 cells/mm vs. 263 cells/mm; P < 0.0001). To determine the effect of PTEN loss on PD-L1 expression, stable cell lines were generated using PTEN short hairpin RNA (shRNA). PTEN knockdown led to significantly higher cell-surface PD-L1 expression and PD-L1 transcripts, suggesting transcriptional regulation. Moreover, phosphoinositide 3-kinase (PI3K) pathway inhibition using the AKT inhibitor MK-2206 or rapamycin resulted in decreased PD-L1 expression, further linking PTEN and PI3K signaling to PD-L1 regulation. Coculture experiments were performed to determine the functional effect of altered PD-L1 expression. Increased PD-L1 cell surface expression by tumor cells induced by PTEN loss led to decreased T-cell proliferation and increased apoptosis. PD-L1 is expressed in 20% of TNBCs, suggesting PD-L1 as a therapeutic target in TNBCs. Because PTEN loss is one mechanism regulating PD-L1 expression, agents targeting the PI3K pathway may increase the antitumor adaptive immune responses. Cancer Immunol Res; 2(4); 361–70. ©2014 AACR.
Data from In Vitro Characterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, and In Vivo Toxicology in Non-Human Primates
Authors: Wang Changyu , Thudium Kent B. , Han Minhua , Wang Xi-Tao , Huang Haichun , Feingersh Diane , Garcia Candy , Wu Yi , Kuhne Michelle , Srinivasan Mohan , Singh Sujata , Wong Susan , Garner Neysa , Leblanc Heidi , Bunch R. Todd , Blanset Diann , Selby Mark J. , Korman Alan J.
Published: March 2024

Abstract
The programmed death-1 (PD-1) receptor serves as an immunologic checkpoint, limiting bystander tissue damage and preventing the development of autoimmunity during inflammatory responses. PD-1 is expressed by activated T cells and downmodulates T-cell effector functions upon binding to its ligands, PD-L1 and PD-L2, on antigen-presenting cells. In patients with cancer, the expression of PD-1 on tumor-infiltrating lymphocytes and its interaction with the ligands on tumor and immune cells in the tumor microenvironment undermine antitumor immunity and support its rationale for PD-1 blockade in cancer immunotherapy. This report details the development and characterization of nivolumab, a fully human IgG4 (S228P) anti-PD-1 receptor-blocking monoclonal antibody. Nivolumab binds to PD-1 with high affinity and specificity, and effectively inhibits the interaction between PD-1 and its ligands. In vitro assays demonstrated the ability of nivolumab to potently enhance T-cell responses and cytokine production in the mixed lymphocyte reaction and superantigen or cytomegalovirus stimulation assays. No in vitro antibody-dependent cell-mediated or complement-dependent cytotoxicity was observed with the use of nivolumab and activated T cells as targets. Nivolumab treatment did not induce adverse immune-related events when given to cynomolgus macaques at high concentrations, independent of circulating anti-nivolumab antibodies where observed. These data provide a comprehensive preclinical characterization of nivolumab, for which antitumor activity and safety have been demonstrated in human clinical trials in various solid tumors. Cancer Immunol Res; 2(9); 846–56. ©2014 AACR.
Data from Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy
Authors: Wu Xinqi , Giobbie-Hurder Anita , Liao Xiaoyun , Connelly Courtney , Connolly Erin M. , Li Jingjing , Manos Michael P. , Lawrence Donald , McDermott David , Severgnini Mariano , Zhou Jun , Gjini Evisa , Lako Ana , Lipschitz Mikel , Pak Christine J. , Abdelrahman Sara , Rodig Scott , Hodi F. Stephen
Published: March 2024

Abstract
Immune checkpoint therapies targeting CTLA-4 and PD-1 have proven effective in cancer treatment. However, the identification of biomarkers for predicting clinical outcomes and mechanisms to overcome resistance remain as critical needs. Angiogenesis is increasingly appreciated as an immune modulator with potential for combinatorial use with checkpoint blockade. Angiopoietin-2 (ANGPT2) is an immune target in patients and is involved in resistance to anti-VEGF treatment with the monoclonal antibody bevacizumab. We investigated the predictive and prognostic value of circulating ANGPT2 in metastatic melanoma patients receiving immune checkpoint therapy. High pretreatment serum ANGPT2 was associated with reduced overall survival in CTLA-4 and PD-1 blockade–treated patients. These treatments also increased serum ANGPT2 in many patients early after treatment initiation, whereas ipilimumab plus bevacizumab treatment decreased serum concentrations. ANGPT2 increases were associated with reduced response and/or overall survival. Ipilimumab increased, and ipilimumab plus bevacizumab decreased, tumor vascular ANGPT2 expression in a subset of patients, which was associated with increased and decreased tumor infiltration by CD68+ and CD163+ macrophages, respectively. In vitro, bevacizumab blocked VEGF-induced ANGPT2 expression in tumor-associated endothelial cells, whereas ANGPT2 increased PD-L1 expression on M2-polarized macrophages. Treatments elicited long-lasting and functional antibody responses to ANGPT2 in a subset of patients receiving clinical benefit. Our findings suggest that serum ANGPT2 may be considered as a predictive and prognostic biomarker for immune checkpoint therapy and may contribute to treatment resistance via increasing proangiogenic and immunosuppressive activities in the tumor microenvironment. Targeting ANGPT2 provides a rational combinatorial approach to improve the efficacy of immune therapy. Cancer Immunol Res; 5(1); 17–28. ©2016 AACR.
Data from Melanoma-Derived Wnt5a Promotes Local Dendritic-Cell Expression of IDO and Immunotolerance: Opportunities for Pharmacologic Enhancement of Immunotherapy
Authors: Holtzhausen Alisha , Zhao Fei , Evans Kathy S. , Tsutsui Masahito , Orabona Ciriana , Tyler Douglas S. , Hanks Brent A.
Published: March 2024

Abstract
The β-catenin signaling pathway has been demonstrated to promote the development of a tolerogenic dendritic cell (DC) population capable of driving regulatory T-cell (Treg) differentiation. Further studies have implicated tolerogenic DCs in promoting carcinogenesis in preclinical models. The molecular mechanisms underlying the establishment of immune tolerance by this DC population are poorly understood, and the methods by which developing cancers can co-opt this pathway to subvert immune surveillance are currently unknown. This work demonstrates that melanoma-derived Wnt5a ligand upregulates the durable expression and activity of the indoleamine 2,3-dioxygenase-1 (IDO) enzyme by local DCs in a manner that depends upon the β-catenin signaling pathway. These data indicate that Wnt5a-conditioned DCs promote the differentiation of Tregs in an IDO-dependent manner, and that this process serves to suppress melanoma immune surveillance. We further show that the genetic silencing of the PORCN membrane–bound O-acyl transferase, which is necessary for melanoma Wnt ligand secretion, enhances antitumor T-cell immunity, and that the pharmacologic inhibition of this enzyme synergistically suppresses melanoma progression when combined with anti–CTLA-4 antibody therapy. Finally, our data suggest that β-catenin signaling activity, based on a target gene expression profile that includes IDO in human sentinel lymph node–derived DCs, is associated with melanoma disease burden and diminished progression-free survival. This work implicates the Wnt–β-catenin signaling pathway as a novel therapeutic target in the melanoma immune microenvironment and demonstrates the potential impact of manipulating DC function as a strategy for optimizing tumor immunotherapy. Cancer Immunol Res; 3(9); 1082–95. ©2015 AACR.
Data from Antitumor Efficacy of Anti-GD2 IgG1 Is Enhanced by Fc Glyco-Engineering
Authors: Xu Hong , Guo Hongfen , Cheung Irene Y. , Cheung Nai-Kong V.
Published: March 2024

Abstract
The affinity of therapeutic antibodies for Fcγ receptors (FcγRs) strongly influences their antitumor potency. To generate antibodies with optimal binding and immunologic efficacy, we compared the affinities of different versions of an IgG1 Fc region that had an altered peptide backbone, altered glycans, or both. To produce IgG1 with glycans that lacked α1,6-fucose, we used CHO cells that were deficient in the enzyme UDP-N-acetylglucosamine: α-3-d-mannoside-β-1,2-N-acetylglucosaminyltransferase I (GnT1), encoded by the MGAT1 gene. Mature N-linked glycans require this enzyme, and without it, CHO cells synthesize antibodies carrying only Man5-GlcNAc2, which were more effective in antibody-dependent cell-mediated cytotoxicity (ADCC). Our engineered IgG1, hu3F8-IgG1, is specific for GD2, a neuroendocrine tumor ganglioside. Its peptide mutant is IgG1-DEL (S239D/I332E/A330L), both produced in wild-type CHO cells. When produced in GnT1-deficient CHO cells, we refer to them as IgG1n and IgG1n-DEL, respectively. Affinities for human FcγRs were measured using Biacore T-100 (on CD16 and CD32 polymorphic alleles), their immunologic properties compared for ADCC and complement-mediated cytotoxicity (CMC) in vitro, and pharmacokinetics and antitumor effects were compared in vivo in humanized mice. IgG1n and IgG1n-DEL contained only mannose and acetylglucosamine and had preferential affinity for activating CD16s, over inhibitory CD32B, receptors. In vivo, the antitumor effects of IgG1, IgG1-DEL, and IgG1n-DEL were similar but modest, whereas IgG1n was significantly more effective (P < 0.05). Thus, IgG1n antibodies produced in GnT1-deficient CHO cells may have potential as improved anticancer therapeutics. Cancer Immunol Res; 4(7); 631–8. ©2016 AACR.
Data from Immunotherapy Converts Nonimmunogenic Pancreatic Tumors into Immunogenic Foci of Immune Regulation
Authors: Lutz Eric R. , Wu Annie A. , Bigelow Elaine , Sharma Rajni , Mo Guanglan , Soares Kevin , Solt Sara , Dorman Alvin , Wamwea Anthony , Yager Allison , Laheru Daniel , Wolfgang Christopher L. , Wang Jiang , Hruban Ralph H. , Anders Robert A. , Jaffee Elizabeth M. , Zheng Lei
Published: March 2024

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is considered a “nonimmunogenic” neoplasm. Single-agent immunotherapies have failed to demonstrate significant clinical activity in PDAC and other “nonimmunogenic” tumors, in part due to a complex tumor microenvironment (TME) that provides a formidable barrier to immune infiltration and function. We designed a neoadjuvant and adjuvant clinical trial comparing an irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting, allogeneic PDAC vaccine (GVAX) given as a single agent or in combination with low-dose cyclophosphamide to deplete regulatory T cells (Treg) as a means to study how the TME is altered by immunotherapy. Examination of resected PDACs revealed the formation of vaccine-induced intratumoral tertiary lymphoid aggregates in 33 of 39 patients 2 weeks after vaccine treatment. Immunohistochemical analysis showed these aggregates to be regulatory structures of adaptive immunity. Microarray analysis of microdissected aggregates identified gene-expression signatures in five signaling pathways involved in regulating immune-cell activation and trafficking that were associated with improved postvaccination responses. A suppressed Treg pathway and an enhanced Th17 pathway within these aggregates were associated with improved survival, enhanced postvaccination mesothelin-specific T-cell responses, and increased intratumoral Teff:Treg ratios. This study provides the first example of immune-based therapy converting a “nonimmunogenic” neoplasm into an “immunogenic” neoplasm by inducing infiltration of T cells and development of tertiary lymphoid structures in the TME. Post-GVAX T-cell infiltration and aggregate formation resulted in the upregulation of immunosuppressive regulatory mechanisms, including the PD-1–PD-L1 pathway, suggesting that patients with vaccine-primed PDAC may be better candidates than vaccine-naïve patients for immune checkpoint and other immunomodulatory therapies. Cancer Immunol Res; 2(7); 616–31. ©2014 AACR.
Data from Durable Complete Response from Metastatic Melanoma after Transfer of Autologous T Cells Recognizing 10 Mutated Tumor Antigens
Authors: Prickett Todd D. , Crystal Jessica S. , Cohen Cyrille J. , Pasetto Anna , Parkhurst Maria R. , Gartner Jared J. , Yao Xin , Wang Rong , Gros Alena , Li Yong F. , El-Gamil Mona , Trebska-McGowan Kasia , Rosenberg Steven A. , Robbins Paul F.
Published: March 2024

Abstract
Immunotherapy treatment of patients with metastatic cancer has assumed a prominent role in the clinic. Durable complete response rates of 20% to 25% are achieved in patients with metastatic melanoma following adoptive cell transfer of T cells derived from metastatic lesions, responses that appear in some patients to be mediated by T cells that predominantly recognize mutated antigens. Here, we provide a detailed analysis of the reactivity of T cells administered to a patient with metastatic melanoma who exhibited a complete response for over 3 years after treatment. Over 4,000 nonsynonymous somatic mutations were identified by whole-exome sequence analysis of the patient's autologous normal and tumor cell DNA. Autologous B cells transfected with 720 mutated minigenes corresponding to the most highly expressed tumor cell transcripts were then analyzed for their ability to stimulate the administered T cells. Autologous tumor-infiltrating lymphocytes recognized 10 distinct mutated gene products, but not the corresponding wild-type products, each of which was recognized in the context of one of three different MHC class I restriction elements expressed by the patient. Detailed clonal analysis revealed that 9 of the top 20 most prevalent clones present in the infused T cells, comprising approximately 24% of the total cells, recognized mutated antigens. Thus, we have identified and enriched mutation-reactive T cells and suggest that such analyses may lead to the development of more effective therapies for the treatment of patients with metastatic cancer. Cancer Immunol Res; 4(8); 669–78. ©2016 AACR.
Data from Clinical Features of Acquired Resistance to Anti–PD-1 Therapy in Advanced Melanoma
Authors: Wang Daniel Y. , Eroglu Zeynep , Ozgun Alpaslan , Leger Paul D. , Zhao Shilin , Ye Fei , Luke Jason J. , Joseph Richard W. , Haq Rizwan , Ott Patrick A. , Hodi F. Stephen , Sosman Jeffrey A. , Johnson Douglas B. , Buchbinder Elizabeth I.
Published: March 2024

Abstract
Anti–PD-1 therapy has improved clinical outcomes in advanced melanoma, but most patients experience intrinsic resistance. Responding patients can develop acquired resistance to anti–PD-1. We retrospectively reviewed 488 patients treated with anti–PD-1 from three academic centers and identified 36 patients with acquired resistance, defined as disease progression following objective response. The incidence, timing, disease sites, post-progression survival (PPS), and outcomes were evaluated descriptively. The acquired resistance cohort consisted of 67% with more than 1 feature of poor prognosis (stage M1c, elevated LDH, or brain metastasis), and 67% had previously received ipilimumab. Partial and complete responses were achieved in 89% (n = 32) and 11% (n = 4) of patients, respectively, and median time to resistance (progression-free survival; PFS) was 11.1 months (range 4.3–32.8 months). Most progression was isolated (78% of patients, n = 28) and occurred while receiving therapy (78%, n = 28). The median PPS was 12.8 months (range 0.1–51.8 months), and the median overall survival was 33.7 months. Among isolated progressors, 15 received localized therapy (12 with surgery, 3 with radiation). Patients with isolated versus systemic progression exhibited a trend for improved PPS (P = 0.081), and patients with an initial PFS ≥ 15 months showed significant PPS improvement (P = 0.036). Two patients experienced subsequent responses to anti–PD-1 resumption. In conclusion, acquired resistance to anti–PD-1 was frequently associated with excellent clinical outcomes and often presented as isolated progression amenable to localized therapy (surgery or radiation) or systemic progression sensitive to therapy resumption. Cancer Immunol Res; 5(5); 357–62. ©2017 AACR.
Data from Bevacizumab plus Ipilimumab in Patients with Metastatic Melanoma
Authors: Hodi F. Stephen , Lawrence Donald , Lezcano Cecilia , Wu Xinqi , Zhou Jun , Sasada Tetsuro , Zeng Wanyong , Giobbie-Hurder Anita , Atkins Michael B. , Ibrahim Nageatte , Friedlander Philip , Flaherty Keith T. , Murphy George F. , Rodig Scott , Velazquez Elsa F. , Mihm Martin C. , Russell Sara , DiPiro Pamela J. , Yap Jeffrey T. , Ramaiya Nikhil , Van den Abbeele Annick D. , Gargano Maria , McDermott David
Published: March 2024

Abstract
Ipilimumab improves survival in advanced melanoma and can induce immune-mediated tumor vasculopathy. Besides promoting angiogenesis, vascular endothelial growth factor (VEGF) suppresses dendritic cell maturation and modulates lymphocyte endothelial trafficking. This study investigated the combination of CTLA4 blockade with ipilimumab and VEGF inhibition with bevacizumab. Patients with metastatic melanoma were treated in four dosing cohorts of ipilimumab (3 or 10 mg/kg) with four doses at 3-week intervals and then every 12 weeks, and bevacizumab (7.5 or 15 mg/kg) every 3 weeks. Forty-six patients were treated. Inflammatory events included giant cell arteritis (n = 1), hepatitis (n = 2), and uveitis (n = 2). On-treatment tumor biopsies revealed activated vessel endothelium with extensive CD8+ and macrophage cell infiltration. Peripheral blood analyses demonstrated increases in CCR7+/−/CD45RO+ cells and anti-galectin antibodies. Best overall response included 8 partial responses, 22 instances of stable disease, and a disease-control rate of 67.4%. Median survival was 25.1 months. Bevacizumab influences changes in tumor vasculature and immune responses with ipilimumab administration. The combination of bevacizumab and ipilimumab can be safely administered and reveals VEGF-A blockade influences on inflammation, lymphocyte trafficking, and immune regulation. These findings provide a basis for further investigating the dual roles of angiogenic factors in blood vessel formation and immune regulation, as well as future combinations of antiangiogenesis agents and immune checkpoint blockade. Cancer Immunol Res; 2(7); 632–42. ©2014 AACR.
Data from Long-term Benefit of PD-L1 Blockade in Lung Cancer Associated with JAK3 Activation
Authors: Van Allen Eliezer M. , Golay Hadrien G. , Liu Yan , Koyama Shohei , Wong Karrie , Taylor-Weiner Amaro , Giannakis Marios , Harden Maegan , Rojas-Rudilla Vanesa , Chevalier Aaron , Thai Tran , Lydon Christine , Mach Stacy , Avila Ada G. , Wong Joshua A. , Rabin Alexandra R. , Helmkamp Joshua , Sholl Lynette , Carter Scott L. , Oxnard Geoffrey , Janne Pasi , Getz Gad , Lindeman Neal , Hammerman Peter S. , Garraway Levi A. , Hodi F. Stephen , Rodig Scott J. , Dranoff Glenn , Wong Kwok-Kin , Barbie David A.
Published: March 2024

Abstract
PD-1 immune checkpoint blockade occasionally results in durable clinical responses in advanced metastatic cancers. However, mechanism-based predictors of response to this immunotherapy remain incompletely characterized. We performed comprehensive genomic profiling on a tumor and germline sample from a patient with refractory lung adenocarcinoma who achieved marked long-term clinical benefit from anti–PD-L1 therapy. We discovered activating somatic and germline amino acid variants in JAK3 that promoted PD-L1 induction in lung cancer cells and in the tumor immune microenvironment. These findings suggest that genomic alterations that deregulate cytokine receptor signal transduction could contribute to PD-L1 activation and engagement of the PD-1 immune checkpoint in lung cancer. Cancer Immunol Res; 3(8); 855–63. ©2015 AACR.
Data from Type I Cytokines Synergize with Oncogene Inhibition to Induce Tumor Growth Arrest
Authors: Acquavella Nicolas , Clever David , Yu Zhiya , Roelke-Parker Melody , Palmer Douglas C. , Xi Liqiang , Pflicke Holger , Ji Yun , Gros Alena , Hanada Ken-ichi , Goldlust Ian S. , Mehta Gautam U. , Klebanoff Christopher A. , Crompton Joseph G. , Sukumar Madhusudhanan , Morrow James J. , Franco Zulmarie , Gattinoni Luca , Liu Hui , Wang Ena , Marincola Francesco , Stroncek David F. , Lee Chyi-Chia R. , Raffeld Mark , Bosenberg Marcus W. , Roychoudhuri Rahul , Restifo Nicholas P.
Published: March 2024

Abstract
Both targeted inhibition of oncogenic driver mutations and immune-based therapies show efficacy in treatment of patients with metastatic cancer, but responses can be either short lived or incompletely effective. Oncogene inhibition can augment the efficacy of immune-based therapy, but mechanisms by which these two interventions might cooperate are incompletely resolved. Using a novel transplantable BRAFV600E-mutant murine melanoma model (SB-3123), we explored potential mechanisms of synergy between the selective BRAFV600E inhibitor vemurafenib and adoptive cell transfer (ACT)–based immunotherapy. We found that vemurafenib cooperated with ACT to delay melanoma progression without significantly affecting tumor infiltration or effector function of endogenous or adoptively transferred CD8+ T cells, as previously observed. Instead, we found that the T-cell cytokines IFNγ and TNFα synergized with vemurafenib to induce cell-cycle arrest of tumor cells in vitro. This combinatorial effect was recapitulated in human melanoma–derived cell lines and was restricted to cancers bearing a BRAFV600E mutation. Molecular profiling of treated SB-3123 indicated that the provision of vemurafenib promoted the sensitization of SB-3123 to the antiproliferative effects of T-cell effector cytokines. The unexpected finding that immune cytokines synergize with oncogene inhibitors to induce growth arrest has major implications for understanding cancer biology at the intersection of oncogenic and immune signaling and provides a basis for design of combinatorial therapeutic approaches for patients with metastatic cancer. Cancer Immunol Res; 3(1); 37–47. ©2014 AACR.

See related commentary by Riddell, p. 23
Data from SLC45A2: A Melanoma Antigen with High Tumor Selectivity and Reduced Potential for Autoimmune Toxicity
Authors: Park Jungsun , Talukder Amjad H. , Lim Seon A. , Kim Kwanghee , Pan Ke , Melendez Brenda , Bradley Sherille D. , Jackson Kyle R. , Khalili Jahan S. , Wang Junmei , Creasy Caitlin , Pan Bih-Fang , Woodman Scott E. , Bernatchez Chantale , Hawke David , Hwu Patrick , Lee Kyung-Mi , Roszik Jason , Lizée Gregory , Yee Cassian
Published: March 2024

Abstract
Cytotoxic T lymphocyte (CTL)–based immunotherapies have had remarkable success at generating objective clinical responses in patients with advanced metastatic melanoma. Although the melanocyte differentiation antigens (MDA) MART-1, PMEL, and tyrosinase were among the first melanoma tumor-associated antigens identified and targeted with immunotherapy, expression within normal melanocytes of the eye and inner ear can elicit serious autoimmune side effects, thus limiting their clinical potential as CTL targets. Using a tandem mass spectrometry (MS) approach to analyze the immunopeptidomes of 55 melanoma patient–derived cell lines, we identified a number of shared HLA class I–bound peptides derived from the melanocyte-specific transporter protein SLC45A2. Antigen-specific CTLs generated against HLA-A*0201- and HLA-A*2402–restricted SLC45A2 peptides effectively killed a majority of HLA-matched cutaneous, uveal, and mucosal melanoma cell lines tested (18/25). CTLs specific for SLC45A2 showed significantly reduced recognition of HLA-matched primary melanocytes that were, conversely, robustly killed by MART1- and PMEL-specific T cells. Transcriptome analysis revealed that SLC45A2 mRNA expression in normal melanocytes was less than 2% that of other MDAs, therefore providing a more favorable melanoma-to-melanocyte expression ratio. Expression of SLC45A2 and CTL sensitivity could be further upregulated in BRAF(V600E)-mutant melanoma cells upon treatment with BRAF or MEK inhibitors, similarly to other MDAs. Taken together, our study demonstrates the feasibility of using tandem MS as a means of discovering shared immunogenic tumor-associated epitopes and identifies SLC45A2 as a promising immunotherapeutic target for melanoma with high tumor selectivity and reduced potential for autoimmune toxicity. Cancer Immunol Res; 5(8); 618–29. ©2017 AACR.
Data from Augmentation of CAR T-cell Trafficking and Antitumor Efficacy by Blocking Protein Kinase A Localization
Authors: Newick Kheng , O'Brien Shaun , Sun Jing , Kapoor Veena , Maceyko Steven , Lo Albert , Puré Ellen , Moon Edmund , Albelda Steven M.
Published: March 2024

Abstract
Antitumor treatments based on the infusion of T cells expressing chimeric antigen receptors (CAR T cells) are still relatively ineffective for solid tumors, due to the presence of immunosuppressive mediators [such as prostaglandin E2 (PGE2) and adenosine] and poor T-cell trafficking. PGE2 and adenosine activate protein kinase A (PKA), which then inhibits T-cell receptor (TCR) activation. This inhibition process requires PKA to localize to the immune synapse via binding to the membrane protein ezrin. We generated CAR T cells that expressed a small peptide called the “regulatory subunit I anchoring disruptor” (RIAD) that inhibits the association of PKA with ezrin, thus blunting the negative effects of PKA on TCR activation. After exposure to PGE2 or adenosine in vitro, CAR-RIAD T cells showed increased TCR signaling, released more cytokines, and showed enhanced killing of tumor cells compared with CAR T cells. When injected into tumor-bearing mice, the antitumor efficacy of murine and human CAR-RIAD T cells was enhanced compared with that of CAR T cells, due to resistance to tumor-induced hypofunction and increased T-cell infiltration of established tumors. Subsequent in vitro assays showed that both mouse and human CAR-RIAD cells migrated more efficiently than CAR cells did in response to the chemokine CXCL10 and also had better adhesion to various matrices. Thus, the intracellular addition of the RIAD peptide to adoptively transferred CAR T cells augments their efficacy by increasing their effector function and by improving trafficking into tumor sites. This treatment strategy, therefore, shows potential clinical application for treating solid tumors. Cancer Immunol Res; 4(6); 541–51. ©2016 AACR.
Data from Phase I/II Study of Metastatic Melanoma Patients Treated with Nivolumab Who Had Progressed after Ipilimumab
Authors: Weber Jeffrey , Gibney Geoffrey , Kudchadkar Ragini , Yu Bin , Cheng Pingyan , Martinez Alberto J. , Kroeger Jodie , Richards Allison , McCormick Lori , Moberg Valerie , Cronin Heather , Zhao Xiuhua , Schell Michael , Chen Yian Ann
Published: March 2024

Abstract
The checkpoint inhibitor nivolumab is active in patients with metastatic melanoma who have failed ipilimumab. In this phase I/II study, we assessed nivolumab's safety in 92 ipilimumab-refractory patients with unresectable stage III or IV melanoma, including those who experienced grade 3–4 drug-related toxicity to ipilimumab. We report long-term survival, response duration, and biomarkers in these patients after nivolumab treatment (3 mg/kg) every 2 weeks for 24 weeks, then every 12 weeks for up to 2 years, with or without a multipeptide vaccine. The response rate for ipilimumab-refractory patients was 30% (95% CI, 21%–41%). The median duration of response was 14.6 months, median progression-free survival was 5.3 months, and median overall survival was 20.6 months, when patients were followed up for a median of 16 months. One- and 2-year survival rates were 68.4% and 31.2%, respectively. Ipilimumab-naïve and ipilimumab-refractory patients showed no significant difference in survival. The 21 patients with prior grade 3–4 toxicity to ipilimumab that was managed with steroids tolerated nivolumab well, with 62% (95% CI, 38%–82%) having complete or partial responses or stabilized disease at 24 weeks. High numbers of myeloid-derived suppressor cells (MDSC) were associated with poor survival. Thus, survival and long-term safety were excellent in ipilimumab-refractory patients treated with nivolumab. Prior grade 3–4 immune-related adverse effects from ipilimumab were not indicative of nivolumab toxicities, and patients had a high overall rate of remission or stability at 24 weeks. Prospectively evaluating MDSC numbers before treatment could help assess the expected benefit of nivolumab. Cancer Immunol Res; 4(4); 345–53. ©2016 AACR.
Data from Efficacy of a Cancer Vaccine against ALK-Rearranged Lung Tumors
Authors: Voena Claudia , Menotti Matteo , Mastini Cristina , Di Giacomo Filomena , Longo Dario Livio , Castella Barbara , Merlo Maria Elena Boggio , Ambrogio Chiara , Wang Qi , Minero Valerio Giacomo , Poggio Teresa , Martinengo Cinzia , D'Amico Lucia , Panizza Elena , Mologni Luca , Cavallo Federica , Altruda Fiorella , Butaney Mohit , Capelletti Marzia , Inghirami Giorgio , Jänne Pasi A. , Chiarle Roberto
Published: March 2024

Abstract
Non–small cell lung cancer (NSCLC) harboring chromosomal rearrangements of the anaplastic lymphoma kinase (ALK) gene is treated with ALK tyrosine kinase inhibitors (TKI), but the treatment is successful for only a limited amount of time; most patients experience a relapse due to the development of drug resistance. Here, we show that a vaccine against ALK induced a strong and specific immune response that both prophylactically and therapeutically impaired the growth of ALK-positive lung tumors in mouse models. The ALK vaccine was efficacious also in combination with ALK TKI treatment and significantly delayed tumor relapses after TKI suspension. We found that lung tumors containing ALK rearrangements induced an immunosuppressive microenvironment, regulating the expression of PD-L1 on the surface of lung tumor cells. High PD-L1 expression reduced ALK vaccine efficacy, which could be restored by administration of anti–PD-1 immunotherapy. Thus, combinations of ALK vaccine with TKIs and immune checkpoint blockade therapies might represent a powerful strategy for the treatment of ALK-driven NSCLC. Cancer Immunol Res; 3(12); 1333–43. ©2015 AACR.
Data from Immunity to the Vacuolar ATPase Complex Accessory Unit ATP6S1 in Patients with Malignant Melanoma
Authors: Zhou Jun , Gupta Meghna , Wu Xinqi , Yoon Charles , Giobbie-Hurder Anita , Hodi F. Stephen
Published: March 2024

Abstract
The augmentation of high-titer antibodies to ATP6S1 is associated with favorable clinical outcomes in patients who received vaccination with autologous, irradiated tumor cells engineered to secrete GM-CSF and allogeneic bone marrow transplantation. Cellular immune responses to ATP6S1 are unknown. To define its role as an immune target, examination of cellular responses to ATP6S1 and immunity related to current therapies such as checkpoint blockade is needed. We used an overlapping peptide library representing the full-length ATP6S1 protein to screen for cellular responses from the peripheral blood of patients with stage III and IV melanoma. Reactive peptide pools were used to determine the individual peptide activity and epitopes. Recombinant ATP6S1 protein was used in an ELISA to assess potential correlation with humoral immune responses and changes in immunity related to CTLA-4 blockade with ipilimumab in these patients. We observed a broad array of CD4+ and CD8+ cellular responses against ATP6S1, including the identification of several MHC class I and II ATP6S1 epitopes. The generation of specific CD4+ and cytotoxic T cells revealed potent functional capability elicited by ipilimumab treatment in patients with metastatic melanoma, which revealed potent functional capability, including cytokine production, proliferation responsiveness to melanoma cell lines, and tumor-cell killing. Furthermore, the augmented humoral immune responses to ATP6S1 as a function of ipilimumab treatment were associated with beneficial clinical outcomes. These results support the continued development of ATP6S1 as a biomarker and therapeutic target. Cancer Immunol Res; 3(1); 59–67. ©2014 AACR.
Data from Environmental and Genetic Activation of Hypothalamic BDNF Modulates T-cell Immunity to Exert an Anticancer Phenotype
Authors: Xiao Run , Bergin Stephen M. , Huang Wei , Slater Andrew M. , Liu Xianglan , Judd Ryan T. , Lin En-Ju D. , Widstrom Kyle J. , Scoville Steven D. , Yu Jianhua , Caligiuri Michael A. , Cao Lei
Published: March 2024

Abstract
Macroenvironmental factors, including a patient's physical and social environment, play a role in cancer risk and progression. Our previous studies show that living in an enriched environment (EE) providing complex stimuli confers an anticancer phenotype in mice mediated, in part by a specific neuroendocrine axis, with brain-derived neurotrophic factor (BDNF) as the key brain mediator. Here, we investigated how an EE modulated T-cell immunity and its role in the EE-induced anticancer effects. Our data demonstrated that CD8 T cells were required to mediate the anticancer effects of an EE in an orthotropic model of melanoma. In secondary lymphoid tissue (SLT), an EE induced early changes in the phenotype of T-cell populations, characterized by a decrease in the ratio of CD4 T helper to CD8 cytotoxic T lymphocytes (CTL). Overexpression of hypothalamic BDNF reproduced EE-induced T-cell phenotypes in SLT, whereas knockdown of hypothalamic BDNF inhibited EE-induced immune modulation in SLT. Both propranolol and mifepristone blocked the EE-associated modulation of CTLs in SLT, suggesting that both the sympathetic nervous system and the hypothalamic–pituitary–adrenal axis were involved. Our results demonstrated that enhanced anticancer effect of an EE was mediated at least in part through modulation of T-cell immunity and provided support to the emerging concept of manipulating a single gene in the brain to improve cancer immunotherapy. Cancer Immunol Res; 4(6); 488–97. ©2016 AACR.
Data from Quantitative Analysis of Immune Infiltrates in Primary Melanoma
Authors: Gartrell Robyn D. , Marks Douglas K. , Hart Thomas D. , Li Gen , Davari Danielle R. , Wu Alan , Blake Zoë , Lu Yan , Askin Kayleigh N. , Monod Anthea , Esancy Camden L. , Stack Edward C. , Jia Dan Tong , Armenta Paul M. , Fu Yichun , Izaki Daisuke , Taback Bret , Rabadan Raul , Kaufman Howard L. , Drake Charles G. , Horst Basil A. , Saenger Yvonne M.
Published: March 2024

Abstract
Novel methods to analyze the tumor microenvironment (TME) are urgently needed to stratify melanoma patients for adjuvant immunotherapy. Tumor-infiltrating lymphocyte (TIL) analysis, by conventional pathologic methods, is predictive but is insufficiently precise for clinical application. Quantitative multiplex immunofluorescence (qmIF) allows for evaluation of the TME using multiparameter phenotyping, tissue segmentation, and quantitative spatial analysis (qSA). Given that CD3+CD8+ cytotoxic lymphocytes (CTLs) promote antitumor immunity, whereas CD68+ macrophages impair immunity, we hypothesized that quantification and spatial analysis of macrophages and CTLs would correlate with clinical outcome. We applied qmIF to 104 primary stage II to III melanoma tumors and found that CTLs were closer in proximity to activated (CD68+HLA-DR+) macrophages than nonactivated (CD68+HLA-DR−) macrophages (P < 0.0001). CTLs were further in proximity from proliferating SOX10+ melanoma cells than nonproliferating ones (P < 0.0001). In 64 patients with known cause of death, we found that high CTL and low macrophage density in the stroma (P = 0.0038 and P = 0.0006, respectively) correlated with disease-specific survival (DSS), but the correlation was less significant for CTL and macrophage density in the tumor (P = 0.0147 and P = 0.0426, respectively). DSS correlation was strongest for stromal HLA-DR+ CTLs (P = 0.0005). CTL distance to HLA-DR− macrophages associated with poor DSS (P = 0.0016), whereas distance to Ki67− tumor cells associated inversely with DSS (P = 0.0006). A low CTL/macrophage ratio in the stroma conferred a hazard ratio (HR) of 3.719 for death from melanoma and correlated with shortened overall survival (OS) in the complete 104 patient cohort by Cox analysis (P = 0.009) and merits further development as a biomarker for clinical application. Cancer Immunol Res; 6(4); 481–93. ©2018 AACR.
Data from Anti–CTLA-4 Activates Intratumoral NK Cells and Combined with IL15/IL15Rα Complexes Enhances Tumor Control
Authors: Sanseviero Emilio , O’Brien Erin M. , Karras Jenna R. , Shabaneh Tamer B. , Aksoy Bulent Arman , Xu Wei , Zheng Cathy , Yin Xiangfan , Xu Xiaowei , Karakousis Giorgos C. , Amaravadi Ravi K. , Nam Brian , Turk Mary Jo , Hammerbacher Jeff , Rubinstein Mark P. , Schuchter Lynn M. , Mitchell Tara C. , Liu Qin , Stone Erica L.
Published: March 2024

Abstract
Antibodies targeting CTLA-4 induce durable responses in some patients with melanoma and are being tested in a variety of human cancers. However, these therapies are ineffective for a majority of patients across tumor types. Further understanding the immune alterations induced by these therapies may enable the development of novel strategies to enhance tumor control and biomarkers to identify patients most likely to respond. In several murine models, including colon26, MC38, CT26, and B16 tumors cotreated with GVAX, anti–CTLA-4 efficacy depends on interactions between the Fc region of CTLA-4 antibodies and Fc receptors (FcR). Anti–CTLA-4 binding to FcRs has been linked to depletion of intratumoral T regulatory cells (Treg). In agreement with previous studies, we found that Tregs infiltrating CT26, B16-F1, and autochthonous BrafV600EPten−/− melanoma tumors had higher expression of surface CTLA-4 (sCTLA-4) than other T-cell subsets, and anti–CTLA-4 treatment led to FcR-dependent depletion of Tregs infiltrating CT26 tumors. This Treg depletion coincided with activation and degranulation of intratumoral natural killer cells. Similarly, in non–small cell lung cancer (NSCLC) and melanoma patient-derived tumor tissue, Tregs had higher sCTLA-4 expression than other intratumoral T-cell subsets, and Tregs infiltrating NSCLC expressed more sCTLA-4 than circulating Tregs. Patients with cutaneous melanoma who benefited from ipilimumab, a mAb targeting CTLA-4, had higher intratumoral CD56 expression, compared with patients who received little to no benefit from this therapy. Furthermore, using the murine CT26 model we found that combination therapy with anti–CTLA-4 plus IL15/IL15Rα complexes enhanced tumor control compared with either monotherapy.