bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from PD-1 Expression on Peripheral Blood Cells Increases with Stage in Renal Cell Carcinoma Patients and Is Rapidly Reduced after Surgical Tumor Resection
Authors: MacFarlane Alexander W. , Jillab Mowafaq , Plimack Elizabeth R. , Hudes Gary R. , Uzzo Robert G. , Litwin Samuel , Dulaimi Essel , Al-Saleem Tahseen , Campbell Kerry S.
Published: March 2024

Abstract
Programmed death-1 (PD-1) receptor is an inhibitory receptor on hematopoietic cells that can negatively regulate immune responses, particularly responses to tumors, which often upregulate PD-1 ligands. PD-1/PD-1 ligand blocking antibodies can reverse the inhibition and show significant therapeutic promise in treating renal cell carcinoma (RCC), lung cancer, and melanoma. While PD-1 expression on tumor-infiltrating lymphocytes has been associated with poor outcome in RCC, we sought to define immune cell biomarkers, including PD-1, on peripheral blood mononuclear cells (PBMC) that could predict disease progression of RCC patients before and after nephrectomy. We analyzed expression of numerous immune cell markers on fresh PBMCs from 90 RCC patients preoperatively and 25 age-matched healthy controls by 10-color flow cytometry. Postoperative blood samples were also analyzed from 23 members of the RCC patient cohort. The most striking phenotypic immune biomarker in RCC patients was a significant increase in PD-1 expression on certain PBMCs in a subset of patients. Increased PD-1 expression on CD14bright myelomonocytic cells, effector T cells, and natural killer (NK) cells correlated to disease stage, and expression was significantly reduced on all cell types soon after surgical resection of the primary tumor. The results indicate that PD-1 expression on fresh peripheral blood leukocytes may provide a useful indicator of RCC disease progression. Furthermore, measuring PD-1 levels in peripheral blood may assist in identifying patients likely to respond to PD-1 blocking antibodies, and these therapies may be most effective before and immediately after surgical resection of the primary tumor, when PD-1 expression is most prominent. Cancer Immunol Res; 2(4); 320–31. ©2013 AACR.
Data from Post-Sepsis State Induces Tumor-Associated Macrophage Accumulation through CXCR4/CXCL12 and Favors Tumor Progression in Mice
Authors: Mota José M. , Leite Caio A. , Souza Lucas E. , Melo Paulo H. , Nascimento Daniele C. , de-Deus-Wagatsuma Virginia M. , Temporal Jessica , Figueiredo Florêncio , Noushmehr Houtan , Alves-Filho José C. , Cunha Fernando Q. , Rego Eduardo M.
Published: March 2024

Abstract
Survivors from sepsis are in an immunosuppressed state that is associated with higher long-term mortality and risk of opportunistic infections. Whether these factors contribute to neoplastic proliferation, however, remains unclear. Tumor-associated macrophages (TAM) can support malignant cell proliferation, survival, and angiogenesis. We addressed the relationship between the post-sepsis state, tumor progression and TAM accumulation, and phenotypic and genetic profile, using a mouse model of sepsis resolution and then B16 melanoma in mice. In addition, we measured the serum concentrations of TNFα, TGFβ, CCL2, and CXCL12 and determined the effect of in vivo CXCR4/CXCL12 inhibition in this context. Mice that survived sepsis showed increased tumor progression both in the short and long term, and survival times were shorter. TAM accumulation, TAM local proliferation, and serum concentrations of TGFβ, CXCL12, and TNFα were increased. Naïve mice inoculated with B16 together with macrophages from post-sepsis mice also had faster tumor progression and shorter survival. Post-sepsis TAMs had less expression of MHC-II and leukocyte activation-related genes. Inhibition of CXCR4/CXCL12 prevented the post-sepsis–induced tumor progression, TAM accumulation, and TAM in situ proliferation. Collectively, our data show that the post-sepsis state was associated with TAM accumulation through CXCR4/CXCL12, which contributed to B16 melanoma progression. Cancer Immunol Res; 4(4); 312–22. ©2016 AACR.
Data from Primary Tumors Limit Metastasis Formation through Induction of IL15-Mediated Cross-Talk between Patrolling Monocytes and NK Cells
Authors: Kubo Hiroshi , Mensurado Sofia , Gonçalves-Sousa Natacha , Serre Karine , Silva-Santos Bruno
Published: March 2024

Abstract
Metastases are responsible for the vast majority of cancer-related deaths. Although tumor cells can become invasive early during cancer progression, metastases formation typically occurs as a late event. How the immune response to primary tumors may dictate this outcome remains poorly understood, which hampers our capacity to manipulate it therapeutically. Here, we used a two-step experimental model, based on the highly aggressive B16F10 melanoma, that temporally segregates the establishment of primary tumors (subcutaneously) and the formation of lung metastases (from intravenous injection). This allowed us to identify a protective innate immune response induced by primary tumors that inhibits experimental metastasis. We found that in the presence of primary tumors, increased numbers of natural killer (NK) cells with enhanced IFNγ, granzyme B, and perforin production were recruited to the lung upon metastasis induction. These changes were mirrored by a local accumulation of patrolling monocytes and macrophages with high expression of MHC class II and NOS2. Critically, the protective effect on metastasis was lost upon patrolling monocyte or NK cell depletion, IL15 neutralization, or IFNγ ablation. The combined analysis of these approaches allowed us to establish a hierarchy in which patrolling monocytes, making IL15 in response to primary tumors, activate NK cells and IFNγ production that then inhibit lung metastasis formation. This work identifies an innate cell network and the molecular determinants responsible for “metastasis immunosurveillance,” providing support for using the key molecular mediator, IL15, to improve immunotherapeutic outcomes. Cancer Immunol Res; 5(9); 812–20. ©2017 AACR.
Data from Antibody-Dependent Cellular Cytotoxicity Activity of a Novel Anti–PD-L1 Antibody Avelumab (MSB0010718C) on Human Tumor Cells
Authors: Boyerinas Benjamin , Jochems Caroline , Fantini Massimo , Heery Christopher R. , Gulley James L. , Tsang Kwong Yok , Schlom Jeffrey
Published: March 2024

Abstract
Several anti–PD-1/PD-L1 monoclonal antibodies (mAb) are currently providing evidence of clinical benefit in subsets of cancer patients. The mode of action of these mAbs is to inhibit PD-1 on immune cells interacting with PD-L1 on tumor cells. These mAbs are either designed or engineered to eliminate antibody-dependent cell-mediated cytotoxicity (ADCC), which, however, has been implicated as an important mechanism in several highly effective mAb-mediated cancer therapies. A fully human anti–PD-L1 mAb would potentially be able to block PD-1/PD-L1 interactions and also mediate the ADCC lysis of tumor cells. MSB0010718C (designated avelumab) is a fully human IgG1 anti–PD-L1 mAb. The studies reported here demonstrate (i) the ability of avelumab to lyse a range of human tumor cells in the presence of PBMC or NK effectors; (ii) IFNγ can enhance tumor cell PD-L1 expression and, in some cases, enhance ADCC tumor cell lysis; (iii) purified NK cells are potent effectors for avelumab; (iv) similar levels of avelumab-mediated ADCC lysis of tumor cells are seen using purified NK as effectors from either healthy donors or cancer patients; (v) very low levels of avelumab-mediated lysis are seen using whole PBMCs as targets; this finding complements results seen in analyses of PBMC subsets of patients receiving avelumab; and (vi) the addition of IL12 to NK cells greatly enhances avelumab-mediated ADCC. These studies thus provide an additional mode of action for an anti–PD-L1 mAb and support the rationale for further studies to enhance avelumab-mediated ADCC activity. Cancer Immunol Res; 3(10); 1148–57. ©2015 AACR.
Data from Liver Metastasis and Treatment Outcome with Anti-PD-1 Monoclonal Antibody in Patients with Melanoma and NSCLC
Authors: Tumeh Paul C. , Hellmann Matthew D. , Hamid Omid , Tsai Katy K. , Loo Kimberly L. , Gubens Matthew A. , Rosenblum Michael , Harview Christina L. , Taube Janis M. , Handley Nathan , Khurana Neharika , Nosrati Adi , Krummel Matthew F. , Tucker Andrew , Sosa Eduardo V. , Sanchez Phillip J. , Banayan Nooriel , Osorio Juan C. , Nguyen-Kim Dan L. , Chang Jeremy , Shintaku I. Peter , Boasberg Peter D. , Taylor Emma J. , Munster Pamela N. , Algazi Alain P. , Chmielowski Bartosz , Dummer Reinhard , Grogan Tristan R. , Elashoff David , Hwang Jimmy , Goldinger Simone M. , Garon Edward B. , Pierce Robert H. , Daud Adil
Published: March 2024

Abstract
We explored the association between liver metastases, tumor CD8+ T-cell count, and response in patients with melanoma or lung cancer treated with the anti-PD-1 antibody, pembrolizumab. The melanoma discovery cohort was drawn from the phase I Keynote 001 trial, whereas the melanoma validation cohort was drawn from Keynote 002, 006, and EAP trials and the non–small cell lung cancer (NSCLC) cohort from Keynote 001. Liver metastasis was associated with reduced response and shortened progression-free survival [PFS; objective response rate (ORR), 30.6%; median PFS, 5.1 months] compared with patients without liver metastasis (ORR, 56.3%; median PFS, 20.1 months) P ≤ 0.0001, and confirmed in the validation cohort (P = 0.0006). The presence of liver metastasis significantly increased the likelihood of progression (OR, 1.852; P < 0.0001). In a subset of biopsied patients (n = 62), liver metastasis was associated with reduced CD8+ T-cell density at the invasive tumor margin (liver metastasis+ group, n = 547 ± 164.8; liver metastasis− group, n = 1,441 ± 250.7; P < 0.016). A reduced response rate and shortened PFS was also observed in NSCLC patients with liver metastasis [median PFS, 1.8 months; 95% confidence interval (CI), 1.4–2.0], compared with those without liver metastasis (n = 119, median PFS, 4.0 months; 95% CI, 2.1–5.1), P = 0.0094. Thus, liver metastatic patients with melanoma or NSCLC that had been treated with pembrolizumab were associated with reduced responses and PFS, and liver metastases were associated with reduced marginal CD8+ T-cell infiltration, providing a potential mechanism for this outcome. Cancer Immunol Res; 5(5); 417–24. ©2017 AACR.
Data from Afucosylated Antibodies Increase Activation of FcγRIIIa-Dependent Signaling Components to Intensify Processes Promoting ADCC
Authors: Liu Scot D. , Chalouni Cecile , Young Judy C. , Junttila Teemu T. , Sliwkowski Mark X. , Lowe John B.
Published: March 2024

Abstract
Antibody-dependent cellular cytotoxicity (ADCC) is a key mechanism by which therapeutic antibodies mediate their antitumor effects. The absence of fucose on the heavy chain of the antibody increases the affinity between the antibody and FcγRIIIa, which results in increased in vitro and in vivo ADCC compared with the fucosylated form. However, the cellular and molecular mechanisms responsible for increased ADCC are unknown. Through a series of biochemical and cellular studies, we find that human natural killer (NK) cells stimulated with afucosylated antibody exhibit enhanced activation of proximal FcγRIIIa signaling and downstream pathways, as well as enhanced cytoskeletal rearrangement and degranulation, relative to stimulation with fucosylated antibody. Furthermore, analysis of the interaction between human NK cells and targets using a high-throughput microscope-based antibody-dependent cytotoxicity assay shows that afucosylated antibodies increase the number of NK cells capable of killing multiple targets and the rate with which targets are killed. We conclude that the increase in affinity between afucosylated antibodies and FcγRIIIa enhances activation of signaling molecules, promoting cytoskeletal rearrangement and degranulation, which, in turn, potentiates the cytotoxic characteristics of NK cells to increase efficiency of ADCC. Cancer Immunol Res; 3(2); 173–83. ©2014 AACR.
Data from Vaccines Combined with Immune Checkpoint Antibodies Promote Cytotoxic T-cell Activity and Tumor Eradication
Authors: Ali Omar A. , Lewin Sarah A. , Dranoff Glenn , Mooney David J.
Published: March 2024

Abstract
We demonstrate that a poly(lactide-co-glycolide) (PLG) cancer vaccine can be used in combination with immune checkpoint antibodies, anti–CTLA-4 or anti–PD-1, to enhance cytotoxic T-cell (CTL) activity and induce the regression of solid B16 tumors in mice. Combination therapy obviated the need for vaccine boosting and significantly skewed intratumoral reactions toward CTL activity, resulting in the regression of B16 tumors up to 50 mm2 in size and 75% survival rates. These data suggest that combining material-based cancer vaccines with checkpoint antibodies has the potential to mediate tumor regression in humans. Cancer Immunol Res; 4(2); 95–100. ©2015 AACR.
Data from Differentiated State of Initiating Tumor Cells Is Key to Distinctive Immune Responses Seen in H-RasG12V–Induced Squamous Tumors
Authors: Podolsky Michael A. , Bailey Jacob T. , Gunderson Andrew J. , Oakes Carrie J. , Breech Kyle , Glick Adam B.
Published: March 2024

Abstract
Heterogeneity in tumor immune responses is a poorly understood yet critical parameter for successful immunotherapy. In two doxycycline-inducible models where oncogenic H-RasG12V is targeted either to the epidermal basal/stem cell layer with a Keratin14-rtTA transgene (K14Ras), or committed progenitor/suprabasal cells with an Involucrin-tTA transgene (InvRas), we observed strikingly distinct tumor immune responses. On threshold doxycycline levels yielding similar Ras expression, tumor latency, and numbers, tumors from K14Ras mice had an immunosuppressed microenvironment, whereas InvRas tumors had a proinflammatory microenvironment. On a Rag1−/− background, InvRas mice developed fewer and smaller tumors that regressed over time, whereas K14Ras mice developed more tumors with shorter latency than Rag1+/+ controls. Adoptive transfer and depletion studies revealed that B-cell and CD4 T-cell cooperation was critical for tumor yield, lymphocyte polarization, and tumor immune phenotype in Rag1+/+ mice of both models. Coculture of tumor-conditioned B cells with CD4 T cells implicated direct contact for Th1 and regulatory T cell (Treg) polarization, and CD40-CD40L for Th1, Th2, and Treg generation, a response not observed from splenic B cells. Anti-CD40L caused regression of InvRas tumors but enhanced growth in K14Ras, whereas a CD40 agonist mAb had opposite effects in each tumor model. These data show that position of tumor-initiating cells within a stratified squamous epithelial tissue provokes distinct B- and CD4 T-cell interactions, which establish unique tumor microenvironments that regulate tumor development and response to immunotherapy. Cancer Immunol Res; 5(3); 198–210. ©2017 AACR.
Data from Streptavidin: A Novel Immunostimulant for the Selection and Delivery of Autologous and Syngeneic Tumor Vaccines
Authors: Weir Chris , Hudson Amanda L. , Moon Elizabeth , Ross Angus , Alexander Miles , Peters Lyndsay , Langova Veronika , Clarke Stephen J. , Pavlakis Nick , Davey Ross , Howell Viive M.
Published: March 2024

Abstract
Induction of antitumor immunity using autologous tumor proteins is an attractive approach to cancer therapy. However, better methods and stimulants to present these autologous proteins back to the immune system are needed. Here, we identify streptavidin as a novel carrier protein and stimulant, and test the efficacy of both syngeneic (rat) and autologous vaccines (dogs) using streptavidin in combination with reduced soluble tumor proteins. Initial syngeneic vaccine studies in the 9L rat glioma model were used to optimize vaccine dose and selectivity. Cytokine and blood analysis was used to monitor the response. Rats receiving two vaccinations of syngeneic tumor vaccine demonstrated a statistically significant (P < 0.05) survival advantage compared with controls (adjuvant only). Notably, vaccination also led to remission rates of between 30% and 60% in the aggressive 9L glioma model. Antibodies to streptavidin were detected in the serum of vaccinated rats; however, antibody levels did not correlate with the response. The cytokine TNF-α was upregulated in vaccine-treated rats, whereas ICAM1 was downregulated. After engraftment, vaccinated rats maintained CD4+, CD8+ T cells, and total lymphocyte levels closer to normal baseline than those in the controls. Twenty-five dogs treated with autologous vaccine preparations using streptavidin as a stimulant showed no adverse reactions, irrespective of additional chemotherapy and other medications. In this study, we developed a novel method for producing syngeneic and autologous vaccines using streptavidin selectivity and immunogenicity. These vaccines show efficacy in the 9L glioma rat model. Safety was also demonstrated in canine patients presenting with cancer treated with autologous vaccine. Cancer Immunol Res; 2(5); 469–79. ©2014 AACR.
Data from IL10R2 Overexpression Promotes IL22/STAT3 Signaling in Colorectal Carcinogenesis
Authors: Khare Vineeta , Paul Gregor , Movadat Oliver , Frick Adrian , Jambrich Manuela , Krnjic Anita , Marian Brigitte , Wrba Friedrich , Gasche Christoph
Published: March 2024

Abstract
The mucosal immune response in the setting of intestinal inflammation contributes to colorectal cancer. IL10 signaling has a central role in gut homeostasis and is impaired in inflammatory bowel disease (IBD). Out of two IL10 receptor subunits, IL10R1 and IL10R2, the latter is shared among the IL10 family of cytokines and activates STAT signaling. STAT3 is oncogenic in colorectal cancer; however, knowledge about IL10 signaling upstream of STAT3 in colorectal cancer is lacking. Here, expression of IL10 signaling genes was examined in matched pairs from normal and tumor tissue from colorectal cancer patients showing overexpression (mRNA, protein) of IL10R2 and STAT3 but not IL10R1. IL10R2 overexpression was related to microsatellite stability. Transient overexpression of IL10R2 in HT29 cells increased proliferation upon ligand activation (IL10 and IL22). IL22, and not IL10, phosphorylated STAT3 along with increased phosphorylation of AKT and ERK. A significantly higher expression of IL22R1 and IL10R2 was also confirmed in a separate cohort of colorectal cancer samples. IL22 expression was elevated in gut mucosa from patients with IBD and colitis-associated cancer, which also exhibited increased expression of IL22R1 but not its coreceptor IL10R2. Overall, these data indicate that overexpression of IL10R2 and STAT3 contributes to colorectal carcinogenesis in microsatellite-stable tumors through IL22/STAT3 signaling. Cancer Immunol Res; 3(11); 1227–35. ©2015 AACR.
Data from Established T Cell–Inflamed Tumors Rejected after Adaptive Resistance Was Reversed by Combination STING Activation and PD-1 Pathway Blockade
Authors: Moore Ellen , Clavijo Paul E. , Davis Ruth , Cash Harrison , Van Waes Carter , Kim Young , Allen Clint
Published: March 2024

Abstract
Patients with head and neck squamous cell carcinoma harbor T cell–inflamed and non–T cell–inflamed tumors. Despite this, only 20% of patients respond to checkpoint inhibitor immunotherapy. Lack of induction of innate immunity through pattern-recognition receptors, such as the stimulator of interferon (IFN) genes (STING) receptor, may represent a significant barrier to the development of effective antitumor immunity. Here, we demonstrate robust control of a T cell–inflamed (MOC1), but not non–T cell–inflamed (MOC2), model of head and neck cancer by activation of the STING pathway with the synthetic cyclic dinucleotide RP,RP dithio-c-di-GMP. Rejection or durable tumor control of MOC1 tumors was dependent upon a functional STING receptor and CD8 T lymphocytes. STING activation resulted in increased tumor microenvironment type 1 and type 2 IFN and greater expression of PD-1 pathway components in vivo. Established MOC1 tumors were rejected and distant tumors abscopally controlled, after adaptive immune resistance had been reversed by the addition of PD-L1 mAb. These findings suggest that PD-1 pathway blockade may reverse adaptive immune resistance following cyclic dinucleotide treatment, enhancing both local and systemic antitumor immunity. Cancer Immunol Res; 4(12); 1061–71. ©2016 AACR.
Data from Long-term Survival and Clinical Benefit from Adoptive T-cell Transfer in Stage IV Melanoma Patients Is Determined by a Four-Parameter Tumor Immune Signature
Authors: Melief Sara M. , Visconti Valeria V. , Visser Marten , van Diepen Merel , Kapiteijn Ellen H.W. , van den Berg Joost H. , Haanen John B.A.G. , Smit Vincent T.H.B.M. , Oosting Jan , van der Burg Sjoerd H. , Verdegaal Els M.E.
Published: March 2024

Abstract
The presence of tumor-infiltrating immune cells is associated with longer survival and a better response to immunotherapy in early-stage melanoma, but a comprehensive study of the in situ immune microenvironment in stage IV melanoma has not been performed. We investigated the combined influence of a series of immune factors on survival and response to adoptive cell transfer (ACT) in stage IV melanoma patients. Metastases of 73 stage IV melanoma patients, 17 of which were treated with ACT, were studied with respect to the number and functional phenotype of lymphocytes and myeloid cells as well as for expression of galectins-1, -3, and -9. Single factors associated with better survival were identified using Kaplan–Meier curves and multivariate Cox regression analyses, and those factors were used for interaction analyses. The results were validated using The Cancer Genome Atlas database. We identified four parameters that were associated with a better survival: CD8+ T cells, galectin-9+ dendritic cells (DC)/DC-like macrophages, a high M1/M2 macrophage ratio, and the expression of galectin-3 by tumor cells. The presence of at least three of these parameters formed an independent positive prognostic factor for long-term survival. Patients displaying this four-parameter signature were found exclusively among patients responding to ACT and were the ones with sustained clinical benefit. Cancer Immunol Res; 5(2); 170–9. ©2017 AACR.
Data from Tumor-Derived α-Fetoprotein Directly Drives Human Natural Killer–Cell Activation and Subsequent Cell Death
Authors: Vujanovic Lazar , Stahl Elizabeth C. , Pardee Angela D. , Geller David A. , Tsung Allan , Watkins Simon C. , Gibson Gregory A. , Storkus Walter J. , Butterfield Lisa H.
Published: March 2024

Abstract
Hepatocellular carcinoma (HCC) patients with reduced natural killer (NK)–cell numbers and function have been shown to have a poor disease outcome. Mechanisms underlying NK-cell deficiency and dysfunction in HCC patients remain largely unresolved. α-Fetoprotein (AFP) is an oncofetal antigen produced by HCC. Previous studies demonstrated that tumor-derived AFP (tAFP) can indirectly impair NK-cell activity by suppressing dendritic cell function. However, a direct tAFP effect on NK cells remains unexplored. The purpose of this study was to examine the ability of cord blood-derived AFP (nAFP) and that of tAFP to directly modulate human NK-cell activity and longevity in vitro. Short-term exposure to tAFP and, especially, nAFP proteins induced a unique proinflammatory, IL2-hyperresponsive phenotype in NK cells as measured by IL1β, IL6, and TNF secretion, CD69 upregulation, and enhanced tumor cell killing. In contrast, extended coculture with tAFP, but not nAFP, negatively affected long-term NK-cell viability. NK-cell activation was directly mediated by the AFP protein itself, whereas their viability was affected by hydrophilic components within the low molecular mass cargo that copurified with tAFP. Identification of the distinct impact of circulating tAFP on NK-cell function and viability may be crucial to developing a strategy to ameliorate HCC patient NK-cell functional deficits. Cancer Immunol Res; 5(6); 493–502. ©2017 AACR.
Data from Stereotactic Radiation Therapy Augments Antigen-Specific PD-1–Mediated Antitumor Immune Responses via Cross-Presentation of Tumor Antigen
Authors: Sharabi Andrew B. , Nirschl Christopher J. , Kochel Christina M. , Nirschl Thomas R. , Francica Brian J. , Velarde Esteban , Deweese Theodore L. , Drake Charles G.
Published: March 2024

Abstract
The immune-modulating effects of radiotherapy (XRT) have gained considerable interest recently, and there have been multiple reports of synergy between XRT and immunotherapy. However, additional preclinical studies are needed to demonstrate the antigen-specific nature of radiation-induced immune responses and elucidate potential mechanisms of synergy with immunotherapy. Here, we demonstrate the ability of stereotactic XRT to induce endogenous antigen-specific immune responses when it is combined with anti–PD-1 checkpoint blockade immunotherapy. Using the small animal radiation research platform (SARRP), image-guided stereotactic XRT delivered to B16-OVA melanoma or 4T1-HA breast carcinoma tumors resulted in the development of antigen-specific T cell– and B cell–mediated immune responses. These immune-stimulating effects of XRT were significantly increased when XRT was combined with either anti–PD-1 therapy or regulatory T cell (Treg) depletion, resulting in improved local tumor control. Phenotypic analyses of antigen-specific CD8 T cells revealed that XRT increased the percentage of antigen-experienced T cells and effector memory T cells. Mechanistically, we found that XRT upregulates tumor-associated antigen–MHC complexes, enhances antigen cross-presentation in the draining lymph node, and increases T-cell infiltration into tumors. These findings demonstrate the ability of XRT to prime an endogenous antigen-specific immune response and provide an additional mechanistic rationale for combining radiation with PD-1 blockade in the clinic. Cancer Immunol Res; 3(4); 345–55. ©2014 AACR.
Data from Macropinocytosis of Nab-paclitaxel Drives Macrophage Activation in Pancreatic Cancer
Authors: Cullis Jane , Siolas Despina , Avanzi Antonina , Barui Sugata , Maitra Anirban , Bar-Sagi Dafna
Published: March 2024

Abstract
Pancreatic cancer is a devastating disease that is largely refractory to currently available treatment strategies. Therapeutic resistance is partially attributed to the dense stromal reaction of pancreatic ductal adenocarcinoma tumors that includes a pervasive infiltration of immunosuppressive (M2) macrophages. Nab-paclitaxel (trade name Abraxane) is a nanoparticle albumin-bound formulation of paclitaxel that, in combination with gemcitabine, is currently the first-line treatment for pancreatic cancer. Here, we show that macrophages internalized nab-paclitaxel via macropinocytosis. The macropinocytic uptake of nab-paclitaxel induced macrophage immunostimulatory (M1) cytokine expression and synergized with IFNγ to promote inducible nitric oxide synthase expression in a TLR4-dependent manner. Nab-paclitaxel was internalized by tumor-associated macrophages in vivo, and therapeutic doses of nab-paclitaxel alone, and in combination with gemcitabine, increased the MHCII+CD80+CD86+ M1 macrophage population. These data revealed an unanticipated role for nab-paclitaxel in macrophage activation and rationalized its potential use to target immune evasion in pancreatic cancer. Cancer Immunol Res; 5(3); 182–90. ©2017 AACR.
Data from Interleukin-6/STAT3 Pathway Signaling Drives an Inflammatory Phenotype in Group A Ependymoma
Authors: Griesinger Andrea M. , Josephson Rebecca J. , Donson Andrew M. , Mulcahy Levy Jean M. , Amani Vladimir , Birks Diane K. , Hoffman Lindsey M. , Furtek Steffanie L. , Reigan Phillip , Handler Michael H. , Vibhakar Rajeev , Foreman Nicholas K.
Published: March 2024

Abstract
Ependymoma (EPN) in childhood is a brain tumor with substantial mortality. Inflammatory response has been identified as a molecular signature of high-risk Group A EPN. To better understand the biology of this phenotype and aid therapeutic development, transcriptomic data from Group A and B EPN patient tumor samples, and additional malignant and normal brain data, were analyzed to identify the mechanism underlying EPN Group A inflammation. Enrichment of IL6 and STAT3 pathway genes were found to distinguish Group A EPN from Group B EPN and other brain tumors, implicating an IL6 activation of STAT3 mechanism. EPN tumor cell growth was shown to be dependent on STAT3 activity, as demonstrated using shRNA knockdown and pharmacologic inhibition of STAT3 that blocked proliferation and induced apoptosis. The inflammatory factors secreted by EPN tumor cells were shown to reprogram myeloid cells, and this paracrine effect was characterized by a significant increase in pSTAT3 and IL8 secretion. Myeloid polarization was shown to be dependent on tumor secretion of IL6, and these effects could be reversed using IL6-neutralizing antibody or IL6 receptor–targeted therapeutic antibody tocilizumab. Polarized myeloid cell production of IL8 drove unpolarized myeloid cells to upregulate CD163 and to produce a number of proinflammatory cytokines. Collectively, these findings indicate that constitutive IL6/STAT3 pathway activation is important in driving tumor growth and inflammatory cross-talk with myeloid cells within the Group A EPN microenvironment. Effective design of Group A–targeted therapy for children with EPN may require reversal of this potentially immunosuppressive and protumor pathway. Cancer Immunol Res; 3(10); 1165–74. ©2015 AACR.
Data from TH2-Polarized CD4+ T Cells and Macrophages Limit Efficacy of Radiotherapy
Authors: Shiao Stephen L. , Ruffell Brian , DeNardo David G. , Faddegon Bruce A. , Park Catherine C. , Coussens Lisa M.
Published: March 2024

Abstract
Radiotherapy and chemotherapy following surgery are mainstays of treatment for breast cancer. Although multiple studies have recently revealed the significance of immune cells as mediators of chemotherapy response in breast cancer, less is known regarding roles for leukocytes as mediating outcomes following radiotherapy. To address this question, we utilized a syngeneic orthotopic murine model of mammary carcinogenesis to investigate if response to radiotherapy could be improved when select immune cells or immune-based pathways in the mammary microenvironment were inhibited. Treatment of mammary tumor–bearing mice with either a neutralizing mAb to colony-stimulating factor-1 (CSF-1) or a small-molecule inhibitor of the CSF-1 receptor kinase (i.e., PLX3397), resulting in efficient macrophage depletion, significantly delayed tumor regrowth following radiotherapy. Delayed tumor growth in this setting was associated with increased presence of CD8+ T cells and reduced presence of CD4+ T cells, the main source of the TH2 cytokine IL4 in mammary tumors. Selective depletion of CD4+ T cells or neutralization of IL4 in combination with radiotherapy phenocopied results following macrophage depletion, whereas depletion of CD8+ T cells abrogated improved response to radiotherapy following these therapies. Analogously, therapeutic neutralization of IL4 or IL13, or IL4 receptor alpha deficiency, in combination with the chemotherapy paclitaxel, resulted in slowed primary mammary tumor growth by CD8+ T-cell–dependent mechanisms. These findings indicate that clinical responses to cytotoxic therapy in general can be improved by neutralizing dominant TH2-based programs driving protumorigenic and immune-suppressive pathways in mammary (breast) tumors to improve outcomes. Cancer Immunol Res; 3(5); 518–25. ©2015 AACR.
Data from Fine-tuning Tumor Immunity with Integrin Trans-regulation
Authors: Cantor Joseph M. , Rose David M. , Slepak Marina , Ginsberg Mark H.
Published: March 2024

Abstract
Inefficient T-cell homing to tissues limits adoptive T-cell immunotherapy of solid tumors. αLβ2 and α4β1 integrins mediate trafficking of T cells into tissues via engagement of ICAM-1 and VCAM-1, respectively. Inhibiting protein kinase A (PKA)–mediated phosphorylation of α4 integrin in cells results in an increase in αLβ2-mediated migration on mixed ICAM-1–VCAM-1 substrates in vitro, a phenomenon termed “integrin trans-regulation.” Here, we created an α4(S988A)-bearing mouse, which precludes PKA-mediated α4 phosphorylation, to examine the effect of integrin trans-regulation in vivo. The α4(S988A) mouse exhibited a dramatic and selective increase in migration of lymphocytes, but not myeloid cells, to sites of inflammation. Importantly, we found that the α4(S988A) mice exhibited a marked increase in T-cell entry into and reduced growth of B16 melanomas, consistent with antitumor roles of infiltrating T cells and progrowth functions of tumor-associated macrophages. Thus, increased α4 trans-regulation of αLβ2 integrin function biases leukocyte emigration toward lymphocytes relative to myeloid cells and enhances tumor immunity. Cancer Immunol Res; 3(6); 661–7. ©2015 AACR.
Data from A Soluble Form of CD80 Enhances Antitumor Immunity by Neutralizing Programmed Death Ligand-1 and Simultaneously Providing Costimulation
Authors: Haile Samuel T. , Horn Lucas A. , Ostrand-Rosenberg Suzanne
Published: March 2024

Abstract
Tumor cells use various methods of immunosuppression to overcome antitumor immunity. One such method is that of programmed death ligand-1 (PD-L1 or B7-H1), which upon binding its receptor PD-1 on T cells triggers apoptotic death of the activated T cells. Overexpression of the costimulatory molecule CD80 on PD-L1+ tumor cells, or inclusion of a soluble form of CD80 (CD80-Fc), maintains the activation of PD-1+–activated T cells. Using T cells from CD28-deficient mice and antibodies to block CD28 on human T cells, we now report that a soluble form of CD80 mediates this effect by simultaneously neutralizing PD-1–PD-L1-mediated immunosuppression and by providing CD80–CD28 costimulation, and is more effective than antibodies to PD-L1 or PD-1 in maintaining IFNγ production by PD-1+ activated T cells. Therefore, soluble CD80 may be a more effective therapeutic than these checkpoint antibodies for facilitating the development and maintenance of antitumor immunity because it has the dual functions of preventing PD-L1–mediated immunosuppression and simultaneously delivering the second signal for T-cell activation. Cancer Immunol Res; 2(7); 610–5. ©2014 AACR.
Data from Intratumoral Delivery of TriMix mRNA Results in T-cell Activation by Cross-Presenting Dendritic Cells
Authors: Van Lint Sandra , Renmans Dries , Broos Katrijn , Goethals Lode , Maenhout Sarah , Benteyn Daphné , Goyvaerts Cleo , Du Four Stephanie , Van der Jeught Kevin , Bialkowski Lukasz , Flamand Véronique , Heirman Carlo , Thielemans Kris , Breckpot Karine
Published: March 2024

Abstract
Modulating the activity of tumor-infiltrating dendritic cells (TiDC) provides opportunities for novel cancer interventions. In this article, we report on our study of the uptake of mRNA by CD8α+ cross-presenting TiDCs upon its intratumoral (i.t.) delivery. We exploited this property to deliver mRNA encoding the costimulatory molecule CD70, the activation stimuli CD40 ligand, and constitutively active Toll-like receptor 4, referred to as TriMix mRNA. We show that TiDCs are reprogrammed to mature antigen-presenting cells that migrate to tumor-draining lymph nodes (TDLN). TriMix stimulated antitumor T-cell responses to spontaneously engulfed cancer antigens, including a neoepitope. We show in various mouse cancer models that i.t. delivery of TriMix mRNA results in systemic therapeutic antitumor immunity. Finally, we show that the induction of antitumor responses critically depends on TiDCs, whereas it only partially depends on TDLNs. As such, we provide a platform and a mechanistic rationale for the clinical testing of i.t. administration of TriMix mRNA. Cancer Immunol Res; 4(2); 146–56. ©2015 AACR.
Data from Clinical Impact of Tumor DNA Repair Expression and T-cell Infiltration in Breast Cancers
Authors: Green Andrew R. , Aleskandarany Mohammed A. , Ali Reem , Hodgson Eleanor Grace , Atabani Suha , De Souza Karen , Rakha Emad A. , Ellis Ian O. , Madhusudan Srinivasan
Published: March 2024

Abstract
Impaired DNA repair drives mutagenicity, which increases neoantigen load and immunogenicity. We investigated the expression of proteins involved in the DNA damage response (ATM, Chk2), double-strand break repair (BRCA1, BLM, WRN, RECQL4, RECQL5, TOPO2A, DNA-PKcs, Ku70/Ku80), nucleotide excision repair (ERCC1), base excision repair (XRCC1, pol β, FEN1, PARP1), and immune responses (CD8, PD-1, PD-L1, FOXP3) in 1,269 breast cancers and validated our findings in an independent estrogen receptor–negative (ER−) cohort (n = 279). Patients with tumors that expressed low XRCC1, low ATM, and low BRCA1 were not only associated with high numbers of CD8+ tumor-infiltrating lymphocytes, but were also linked to higher grades, high proliferation indexes, presence of dedifferentiated cells, ER− cells, and poor survival (all P ≤ 0.01). PD-1+ or PD-L1+ breast cancers with low XRCC1 were also linked to an aggressive phenotype that was high grade, had high proliferation indexes, contained dedifferentiated cells and ER− (all with P values ≤ 0.01), and poor survival (P = 0.00021 and P = 0.00022, for PD-1+ and PD-L1+ cancers, respectively) including in an independent ER− validation cohort (P = 0.007 and P = 0.047, respectively). We conclude that the interplay between DNA repair, CD8, PD-L1, and PD-1 can promote aggressive tumor phenotypes. XRCC1-directed personalization of immune checkpoint inhibitor therapy may be feasible and warrants further investigation in breast cancer. Cancer Immunol Res; 5(4); 292–9. ©2017 AACR.
Data from Promoter Methylation Modulates Indoleamine 2,3-Dioxygenase 1 Induction by Activated T Cells in Human Breast Cancers
Authors: Noonepalle Satish K. , Gu Franklin , Lee Eun-Joon , Choi Jeong-Hyeon , Han Qimei , Kim Jaejik , Ouzounova Maria , Shull Austin Y. , Pei Lirong , Hsu Pei-Yin , Kolhe Ravindra , Shi Fang , Choi Jiseok , Chiou Katie , Huang Tim H.M. , Korkaya Hasan , Deng Libin , Xin Hong-Bo , Huang Shuang , Thangaraju Muthusamy , Sreekumar Arun , Ambs Stefan , Tang Shou-Ching , Munn David H. , Shi Huidong
Published: March 2024

Abstract
Triple-negative breast cancer (TNBC) cells are modulated in reaction to tumor-infiltrating lymphocytes. However, their specific responses to this immune pressure are unknown. In order to address this question, we first used mRNA sequencing to compare the immunophenotype of the TNBC cell line MDA-MB-231 and the luminal breast cancer cell line MCF7 after both were cocultured with activated human T cells. Despite similarities in the cytokine-induced immune signatures of the two cell lines, MDA-MD-231 cells were able to transcribe more IDO1 than MCF7 cells. The two cell lines had similar upstream JAK/STAT1 signaling and IDO1 mRNA stability. However, using a series of breast cancer cell lines, IFNγ stimulated IDO1 protein expression and enzymatic activity only in ER−, not ER+, cell lines. Treatment with 5-aza-deoxycytidine reversed the suppression of IDO1 expression in MCF7 cells, suggesting that DNA methylation was potentially involved in IDO1 induction. By analyzing several breast cancer datasets, we discovered subtype-specific mRNA and promoter methylation differences in IDO1, with TNBC/basal subtypes exhibiting lower methylation/higher expression and ER+/luminal subtypes exhibiting higher methylation/lower expression. We confirmed this trend of IDO1 methylation by bisulfite pyrosequencing breast cancer cell lines and an independent cohort of primary breast tumors. Taken together, these findings suggest that IDO1 promoter methylation regulates anti-immune responses in breast cancer subtypes and could be used as a predictive biomarker for IDO1 inhibitor–based immunotherapy. Cancer Immunol Res; 5(4); 330–44. ©2017 AACR.
Data from Computational Algorithm-Driven Evaluation of Monocytic Myeloid-Derived Suppressor Cell Frequency for Prediction of Clinical Outcomes
Authors: Kitano Shigehisa , Postow Michael A. , Ziegler Carly G.K. , Kuk Deborah , Panageas Katherine S. , Cortez Czrina , Rasalan Teresa , Adamow Mathew , Yuan Jianda , Wong Philip , Altan-Bonnet Gregoire , Wolchok Jedd D. , Lesokhin Alexander M.
Published: March 2024

Abstract
Evaluation of myeloid-derived suppressor cells (MDSC), a cell type implicated in T-cell suppression, may inform immune status. However, a uniform methodology is necessary for prospective testing as a biomarker. We report the use of a computational algorithm-driven analysis of whole blood and cryopreserved samples for monocytic MDSC (m-MDSC) quantity that removes variables related to blood processing and user definitions. Applying these methods to samples from patients with melanoma identifies differing frequency distribution of m-MDSC relative to that in healthy donors. Patients with a pretreatment m-MDSC frequency outside a preliminary definition of healthy donor range (<14.9%) were significantly more likely to achieve prolonged overall survival following treatment with ipilimumab, an antibody that promotes T-cell activation and proliferation. m-MDSC frequencies were inversely correlated with peripheral CD8+ T-cell expansion following ipilimumab. Algorithm-driven analysis may enable not only development of a novel pretreatment biomarker for ipilimumab therapy, but also prospective validation of peripheral blood m-MDSCs as a biomarker in multiple disease settings. Cancer Immunol Res; 2(8); 812–21. ©2014 AACR.
Data from Nonclassical Antigen-Processing Pathways Are Required for MHC Class II–Restricted Direct Tumor Recognition by NY-ESO-1–Specific CD4+ T Cells
Authors: Matsuzaki Junko , Tsuji Takemasa , Luescher Immanuel , Old Lloyd J. , Shrikant Protul , Gnjatic Sacha , Odunsi Kunle
Published: March 2024

Abstract
Tumor antigen–specific CD4+ T cells that directly recognize cancer cells are important for orchestrating antitumor immune responses at the local tumor sites. However, the mechanisms of direct MHC class II (MHC-II) presentation of intracellular tumor antigen by cancer cells are poorly understood. We found that two functionally distinct subsets of CD4+ T cells were expanded after HLA-DPB1*04 (DP04)-binding NY-ESO-1157-170 peptide vaccination in patients with ovarian cancer. Although both subsets recognized exogenous NY-ESO-1 protein pulsed on DP04+ target cells, only one type recognized target cells with intracellular expression of NY-ESO-1. The tumor-recognizing CD4+ T cells more efficiently recognized the short 8–9-mer peptides than the non–tumor-recognizing CD4+ T cells. In addition to endosomal/lysosomal proteases that are typically involved in MHC-II antigen presentation, several pathways in the MHC class I presentation pathways, such as the proteasomal degradation and transporter-associated with antigen-processing–mediated peptide transport, were also involved in the presentation of intracellular NY-ESO-1 on MHC-II. The presentation was inhibited significantly by primaquine, a small molecule that inhibits endosomal recycling, consistent with findings that pharmacologic inhibition of new protein synthesis enhances antigen presentation. Together, our data demonstrate that cancer cells selectively present peptides from intracellular tumor antigens on MHC-II by multiple nonclassical antigen-processing pathways. Harnessing the direct tumor-recognizing ability of CD4+ T cells could be a promising strategy to enhance antitumor immune responses in the immunosuppressive tumor microenvironment. Cancer Immunol Res; 2(4); 341–50. ©2013 AACR.
Data from MIF Is Necessary for Late-Stage Melanoma Patient MDSC Immune Suppression and Differentiation
Authors: Yaddanapudi Kavitha , Rendon Beatriz E. , Lamont Gwyneth , Kim Eun Jung , Al Rayyan Numan , Richie Jamaal , Albeituni Sabrin , Waigel Sabine , Wise Ashley , Mitchell Robert A.
Published: March 2024

Abstract
Highly aggressive cancers “entrain” innate and adaptive immune cells to suppress antitumor lymphocyte responses. Circulating myeloid-derived suppressor cells (MDSC) constitute the bulk of monocytic immunosuppressive activity in late-stage melanoma patients. Previous studies revealed that monocyte-derived macrophage migration inhibitory factor (MIF) is necessary for the immunosuppressive function of tumor-associated macrophages and MDSCs in mouse models of melanoma. In the current study, we sought to determine whether MIF contributes to human melanoma MDSC induction and T-cell immunosuppression using melanoma patient-derived MDSCs and an ex vivo coculture model of human melanoma-induced MDSC. We now report that circulating MDSCs isolated from late-stage melanoma patients are reliant upon MIF for suppression of antigen-independent T-cell activation and that MIF is necessary for maximal reactive oxygen species generation in these cells. Moreover, inhibition of MIF results in a functional reversion from immunosuppressive MDSC to an immunostimulatory dendritic cell (DC)–like phenotype that is at least partly due to reductions in MDSC prostaglandin E2 (PGE2). These findings indicate that monocyte-derived MIF is centrally involved in human monocytic MDSC induction/immunosuppressive function and that therapeutic targeting of MIF may provide a novel means of inducing antitumor DC responses in late-stage melanoma patients. Cancer Immunol Res; 4(2); 101–12. ©2015 AACR.
Data from IL17A-Mediated Endothelial Breach Promotes Metastasis Formation
Authors: Kulig Paulina , Burkhard Sara , Mikita-Geoffroy Joanna , Croxford Andrew L. , Hövelmeyer Nadine , Gyülvészi Gabor , Gorzelanny Christian , Waisman Ari , Borsig Lubor , Becher Burkhard
Published: March 2024

Abstract
The role of the IL23/IL17A axis in tumor–immune interactions is a matter of controversy. Although some suggest that IL17A-producing T cells (TH17) can suppress tumor growth, others report that IL17A and IL23 accelerate tumor growth. Here, we systematically assessed the impact of IL17A-secreting lymphocytes in several murine models of tumor lung metastasis. Genetic fate mapping revealed that IL17A was secreted within lung metastases predominantly by γδ T cells, whereas TH17 cells were virtually absent. Using different tumor models, we found Il17a−/− mice to consistently develop fewer pulmonary tumor colonies. IL17A specifically increased blood vessel permeability and the expression of E-selectin and VCAM-1 by lung endothelial cells in vivo. In transgenic mice, specific targeting of IL17A to the endothelium increased the number of tumor foci. Moreover, the direct impact of IL17A on lung endothelial cells resulted in impaired endothelial barrier integrity, showing that IL17A promotes the formation of lung metastases through tumor-endothelial transmigration. Cancer Immunol Res; 4(1); 26–32. ©2015 AACR.