bluuebunny/crossref_metadata_2025 huggingface dataset:
Data from CTLA-4 Blockade Synergizes Therapeutically with PARP Inhibition in BRCA1-Deficient Ovarian Cancer
Authors: Higuchi Tomoe , Flies Dallas B. , Marjon Nicole A. , Mantia-Smaldone Gina , Ronner Lukas , Gimotty Phyllis A. , Adams Sarah F.
Published: March 2024

Abstract
Immune checkpoint blockade has shown significant therapeutic efficacy in melanoma and other solid tumors, but results in ovarian cancer have been limited. With evidence that tumor immunogenicity modulates the response to checkpoint blockade, and data indicating that BRCA-deficient ovarian cancers express higher levels of immune response genes, we hypothesized that BRCA− ovarian tumors would be vulnerable to checkpoint blockade. To test this hypothesis, we used an immunocompetent BRCA1-deficient murine ovarian cancer model to compare treatment with CTLA-4 or PD-1/PD-L1 antibodies alone or combined with targeted cytotoxic therapy using a PARP inhibitor. Correlative studies were performed in vitro using human BRCA1− cells. We found that CTLA-4 antibody, but not PD-1/PD-L1 blockade, synergized therapeutically with the PARP inhibitor, resulting in immune-mediated tumor clearance and long-term survival in a majority of animals (P < 0.0001). The survival benefit of this combination was T-cell mediated and dependent on increases in local IFNγ production in the peritoneal tumor environment. Evidence of protective immune memory was observed more than 60 days after completion of therapy. Similar increases in the cytotoxic effect of PARP inhibition in the presence of elevated levels of IFNγ in human BRCA1− cancer cells support the translational potential of this treatment protocol. These results demonstrate that CTLA-4 blockade combined with PARP inhibition induces protective antitumor immunity and significant survival benefit in the BRCA1− tumor model, and support clinical testing of this regimen to improve outcomes for women with hereditary ovarian cancer. Cancer Immunol Res; 3(11); 1257–68. ©2015 AACR.
Data from Exome Sequencing to Predict Neoantigens in Melanoma
Authors: Pritchard Antonia L. , Burel Julie G. , Neller Michelle A. , Hayward Nicholas K. , Lopez J. Alejandro , Fatho Martina , Lennerz Volker , Wölfel Thomas , Schmidt Christopher W.
Published: March 2024

Abstract
The ability to use circulating peripheral blood cells and matched tumor sequencing data as a basis for neoantigen prediction has exciting possibilities for application in the personalized treatment of cancer patients. We have used a high-throughput screening approach, combining whole-exome sequence data, mRNA microarrays, and publicly available epitope prediction algorithm output to identify mutated proteins processed and displayed by patient tumors and recognized by circulating immune cells. Matched autologous melanoma cell lines and peripheral blood mononuclear cells were used to create mixed lymphocyte tumor cell cultures, resulting in an expansion of tumor-reactive T cells to use for mutated peptide screening. Five patients were investigated, three of whom had a durable complete response (CR; 15+ years) in an autologous melanoma-pulsed dendritic cell clinical trial. We identified seven mutated antigens in total that stimulated T-effector memory cells in two of the five patients. While the procedure did not result in clinically applicable neoantigens for all patients, those identified were likely important in tumor clearance, leading to durable CR. The nature of the screening process allows results to be obtained rapidly and is easily applicable to a wide variety of different tumor types. Cancer Immunol Res; 3(9); 992–8. ©2015 AACR.
Data from Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia
Authors: Scharping Nicole E. , Menk Ashley V. , Whetstone Ryan D. , Zeng Xue , Delgoffe Greg M.
Published: March 2024

Abstract
Blockade of the coinhibitory checkpoint molecule PD-1 has emerged as an effective treatment for many cancers, resulting in remarkable responses. However, despite successes in the clinic, most patients do not respond to PD-1 blockade. Metabolic dysregulation is a common phenotype in cancer, but both patients and tumors are metabolically heterogeneous. We hypothesized that the deregulated oxidative energetics of tumor cells present a metabolic barrier to antitumor immunity through the generation of a hypoxic microenvironment and that normalization of tumor hypoxia might improve response to immunotherapy. We show that the murine tumor lines B16 and MC38 differed in their ability to consume oxygen and produce hypoxic environments, which correlated with their sensitivity to checkpoint blockade. Metformin, a broadly prescribed type II diabetes treatment, inhibited oxygen consumption in tumor cells in vitro and in vivo, resulting in reduced intratumoral hypoxia. Although metformin monotherapy had little therapeutic benefit in highly aggressive tumors, combination of metformin with PD-1 blockade resulted in improved intratumoral T-cell function and tumor clearance. Our data suggest tumor hypoxia acts as a barrier to immunotherapy and that remodeling the hypoxic tumor microenvironment has potential to convert patients resistant to immunotherapy into those that receive clinical benefit. Cancer Immunol Res; 5(1); 9–16. ©2016 AACR.
Data from Intratumoral CD3 and CD8 T-cell Densities Associated with Relapse-Free Survival in HCC
Authors: Gabrielson Andrew , Wu Yunan , Wang Hongkun , Jiang Jiji , Kallakury Bhaskar , Gatalica Zoran , Reddy Sandeep , Kleiner David , Fishbein Thomas , Johnson Lynt , Island Eddie , Satoskar Rohit , Banovac Filip , Jha Reena , Kachhela Jaydeep , Feng Perry , Zhang Tiger , Tesfaye Anteneh , Prins Petra , Loffredo Christopher , Marshall John , Weiner Louis , Atkins Michael , He Aiwu Ruth
Published: March 2024

Abstract
Immune cells that infiltrate a tumor may be a prognostic factor for patients who have had surgically resected hepatocellular carcinoma (HCC). The density of intratumoral total (CD3+) and cytotoxic (CD8+) T lymphocytes was measured in the tumor interior and in the invasive margin of 65 stage I to IV HCC tissue specimens from a single cohort. Immune cell density in the interior and margin was converted to a binary score (0, low; 1, high), which was correlated with tumor recurrence and relapse-free survival (RFS). In addition, the expression of programmed death 1 (PD-1) and programmed death ligand 1 (PD-L1) was correlated with the density of CD3+ and CD8+ cells and clinical outcome. High densities of both CD3+ and CD8+ T cells in both the interior and margin, along with corresponding Immunoscores, were significantly associated with a low rate of recurrence (P = 0.007) and a prolonged RFS (P = 0.002). In multivariate logistic regression models adjusted for vascular invasion and cellular differentiation, both CD3+ and CD8+ cell densities predicted recurrence, with odds ratios of 5.8 [95% confidence interval (CI), 1.6–21.8] for CD3+ and 3.9 (95% CI, 1.1–14.1) for CD8+. Positive PD-L1 staining was correlated with high CD3 and CD8 density (P = 0.024 and 0.005, respectively) and predicted a lower rate of recurrence (P = 0.034), as well as prolonged RFS (P = 0.029). Immunoscore and PD-L1 expression, therefore, are useful prognostic markers in patients with HCC who have undergone primary tumor resection. Cancer Immunol Res; 4(5); 419–30. ©2016 AACR.
Data from Phase I Study of Random Healthy Donor–Derived Allogeneic Natural Killer Cell Therapy in Patients with Malignant Lymphoma or Advanced Solid Tumors
Authors: Yang Yaewon , Lim Okjae , Kim Tae Min , Ahn Yong-Oon , Choi Hana , Chung Hyejin , Min Bokyung , Her Jung Hyun , Cho Sung Yoo , Keam Bhumsuk , Lee Se-Hoon , Kim Dong-Wan , Hwang Yu Kyeong , Heo Dae Seog
Published: March 2024

Abstract
Natural killer (NK) cells with mismatched killer cell immunoglobulin-like receptor–ligand pairs have shown efficacy and been proven safe in treatment of cancer patients. Ex vivo–expanded and highly activated NK cells (MG4101) had been generated under good manufacturing practice conditions, which demonstrated potent anticancer activity in vitro and in vivo in preclinical studies. The current phase I clinical trial was designed to evaluate safety and possible clinical efficacy of repetitive administrations of MG4101 derived from random unrelated healthy donors into patients with malignant lymphoma or advanced, recurrent solid tumors. The maximum dose (3 × 107 cells/kg, triple infusion) was tolerable without significant adverse events. Of 17 evaluable patients, 8 patients (47.1%) showed stable disease and 9 (52.9%) showed progressive disease. We also evaluated the capacity of MG4101 to influence host immune responses. Administration of MG4101 augmented NKG2D expression on CD8+ T cells and upregulated chemokines that recruit T cells. In contrast, administration of MG4101 reduced regulatory T cells and myeloid-derived suppressor cells and suppressed TGFβ production. In conclusion, administration of a large number of MG4101 cells was not only safe and feasible, but also exhibited efficacy in maintaining the effector arm of the host immune response. Cancer Immunol Res; 4(3); 215–24. ©2016 AACR.
Data from Systemic Immunotherapy of Non-Muscle Invasive Mouse Bladder Cancer with Avelumab, an Anti–PD-L1 Immune Checkpoint Inhibitor
Authors: Vandeveer Amanda J. , Fallon Jonathan K. , Tighe Robert , Sabzevari Helen , Schlom Jeffrey , Greiner John W.
Published: March 2024

Abstract
Bacillus Calmette–Guerin (BCG) is the standard of care for intravesical therapy for carcinoma in situ and non-muscle invasive, nonmetastatic human urothelial carcinoma. Although the responsiveness to this immunotherapeutic is believed to be linked with (i) a high number of somatic mutations and (ii) a large number of tumor-infiltrating lymphocytes, recent findings of the roles that inhibitory immune receptors and their ligands play in tumor evasion may provide insights into the limitations of the effectiveness of BCG and offer new targets for immune-based therapy. In this study, an aggressive, bioluminescent orthotopic bladder cancer model, MB49 tumor cells transfected with luciferase (MB49luc), was used to study the antitumor effects of avelumab, an antibody to PD-L1. MB49luc murine tumor cells form multifocal tumors on the mucosal wall of the bladder reminiscent of non-muscle invasive, nonmetastatic urothelial carcinomas. MB49luc bladder tumors are highly positive for the expression of PD-L1, and avelumab administration induced significant (P < 0.05) antitumor effects. These antitumor effects were more dependent on the presence of CD4 than CD8 T cells, as determined by in vivo immune cell depletions. The findings suggest that in this bladder tumor model, interruption of the immune-suppressive PD-1/PD-L1 complex releases a local adaptive immune response that, in turn, reduces tumor growth. This bladder tumor model can be used to further identify host antitumor immune mechanisms and evaluate combinations of immune-based therapies for carcinoma in situ and non-muscle invasive, nonmetastatic urothelial carcinoma, to provide the rationale for subsequent clinical studies. Cancer Immunol Res; 4(5); 452–62. ©2016 AACR.
Data from B7-H4 Expression by Nonhematopoietic Cells in the Tumor Microenvironment Promotes Antitumor Immunity
Authors: Rahbar Ramtin , Lin Albert , Ghazarian Magar , Yau Helen-Loo , Paramathas Sangeetha , Lang Philipp A. , Schildknecht Anita , Elford Alisha R. , Garcia-Batres Carlos , Martin Bernard , Berman Hal K. , Leong Wey L. , McCready David R. , Reedijk Michael , Done Susan J. , Miller Naomi , Youngson Bruce , Suh Woong-Kyung , Mak Tak W. , Ohashi Pamela S.
Published: March 2024

Abstract
The B7 family plays a critical role in both positive and negative regulation of immune responses by engaging a variety of receptors on lymphocytes. Importantly, blocking coinhibitory molecules using antibodies specific for CTLA-4 and PD-1 enhances tumor immunity in a subset of patients. Therefore, it is critical to understand the role of different B7 family members since they may be suitable therapeutic targets. B7-H4 is another member that inhibits T-cell function, and it is also upregulated on a variety of tumors and has been proposed to promote tumor growth. Here, we investigate the role of B7-H4 in tumor development and show that B7-H4 expression inhibits tumor growth in two mouse models. Furthermore, we show that B7-H4 expression is required for antitumor immune responses in a mouse model of mammary tumorigenesis. We found that the expression levels of B7-H4 correlate with MHC class I expression in both mouse and human samples. We show that IFNγ upregulates B7-H4 expression on mouse embryo fibroblasts and that the upregulation of B7-H4 on tumors is dependent on T cells. Notably, patients with breast cancer with increased B7-H4 expression show a prolonged time to recurrence. These studies demonstrate a positive role for B7-H4 in promoting antitumor immunity. Cancer Immunol Res; 3(2); 184–95. ©2014 AACR.
Data from Identification of Chimeric Antigen Receptors That Mediate Constitutive or Inducible Proliferation of T Cells
Authors: Frigault Matthew J. , Lee Jihyun , Basil Maria Ciocca , Carpenito Carmine , Motohashi Shinichiro , Scholler John , Kawalekar Omkar U. , Guedan Sonia , McGettigan Shannon E. , Posey Avery D. , Ang Sonny , Cooper Laurence J.N. , Platt Jesse M. , Johnson F. Brad , Paulos Chrystal M. , Zhao Yangbing , Kalos Michael , Milone Michael C. , June Carl H.
Published: March 2024

Abstract
This study compared second-generation chimeric antigen receptors (CAR) encoding signaling domains composed of CD28, ICOS, and 4-1BB (TNFRSF9). Here, we report that certain CARs endow T cells with the ability to undergo long-term autonomous proliferation. Transduction of primary human T cells with lentiviral vectors encoding some of the CARs resulted in sustained proliferation for up to 3 months following a single stimulation through the T-cell receptor (TCR). Sustained numeric expansion was independent of cognate antigen and did not require the addition of exogenous cytokines or feeder cells after a single stimulation of the TCR and CD28. Results from gene array and functional assays linked sustained cytokine secretion and expression of T-bet (TBX21), EOMES, and GATA-3 to the effect. Sustained expression of the endogenous IL2 locus has not been reported in primary T cells. Sustained proliferation was dependent on CAR structure and high expression, the latter of which was necessary but not sufficient. The mechanism involves constitutive signaling through NF-κB, AKT, ERK, and NFAT. The propagated CAR T cells retained a diverse TCR repertoire, and cellular transformation was not observed. The CARs with a constitutive growth phenotype displayed inferior antitumor effects and engraftment in vivo. Therefore, the design of CARs that have a nonconstitutive growth phenotype may be a strategy to improve efficacy and engraftment of CAR T cells. The identification of CARs that confer constitutive or nonconstitutive growth patterns may explain observations that CAR T cells have differential survival patterns in clinical trials. Cancer Immunol Res; 3(4); 356–67. ©2015 AACR.
Data from Arming the Melanoma Sentinel Lymph Node through Local Administration of CpG-B and GM-CSF: Recruitment and Activation of BDCA3/CD141+ Dendritic Cells and Enhanced Cross-Presentation
Authors: Sluijter Berbel J.R. , van den Hout Mari F.C.M. , Koster Bas D. , van Leeuwen Paul A.M. , Schneiders Famke L. , van de Ven Rieneke , Molenkamp Barbara G. , Vosslamber Saskia , Verweij Cornelis L. , van den Tol M. Petrousjka , van den Eertwegh Alfons J.M. , Scheper Rik J. , de Gruijl Tanja D.
Published: March 2024

Abstract
Melanoma-induced suppression of dendritic cells (DC) in the sentinel lymph node (SLN) interferes with the generation of protective antitumor immunity. In an effort to strengthen immune defense against metastatic spread, we performed a three-arm phase II study comprising 28 patients with stage I–II melanoma randomized to receive intradermal injections around the primary tumor excision site of saline or low-dose CpG-B, alone or combined with GM-CSF, before excision of the SLNs. After pathologic examination, 5 patients were diagnosed with stage III melanoma based on the presence of tumor cells in the SLNs. Combined CpG/GM-CSF administration resulted in enhanced maturation of all identifiable conventional (cDC) and plasmacytoid (pDC) DC subsets and selectively induced increased frequencies of SLN-resident BDCA3/CD141+ cDC subsets that also expressed the C-type lectin receptor CLEC9A. Correlative in vivo analyses and in vitro studies provided evidence that these subsets were derived from BDCA3+ cDC precursors in the blood that were recruited to the SLNs in a type I IFN-dependent manner and subsequently matured under the combined influence of CpG and GM-CSF. In line with their reported functional abilities, frequencies of in vivo CpG/GM-CSF–induced BDCA3/CD141+ DCs correlated with increased ex vivo cross-presenting capacity of SLN suspensions. Combined local CpG/GM-CSF delivery thus supports protective antimelanoma immunity through concerted activation of pDC and cDC subsets and recruitment of BDCA3+ cDC subsets with T cell–stimulatory and cross-priming abilities. Cancer Immunol Res; 3(5); 495–505. ©2015 AACR.
Data from Soluble PD-L1 as a Biomarker in Malignant Melanoma Treated with Checkpoint Blockade
Authors: Zhou Jun , Mahoney Kathleen M. , Giobbie-Hurder Anita , Zhao Fengmin , Lee Sandra , Liao Xiaoyun , Rodig Scott , Li Jingjing , Wu Xinqi , Butterfield Lisa H. , Piesche Matthias , Manos Michael P. , Eastman Lauren M. , Dranoff Glenn , Freeman Gordon J. , Hodi F. Stephen
Published: March 2024

Abstract
Blockade of the pathway including programmed death-ligand 1 (PD-L1) and its receptor programmed cell death protein 1 (PD-1) has produced clinical benefits in patients with a variety of cancers. Elevated levels of soluble PD-L1 (sPD-L1) have been associated with worse prognosis in renal cell carcinoma and multiple myeloma. However, the regulatory roles and function of sPD-L1 particularly in connection with immune checkpoint blockade treatment are not fully understood. We identified four splice variants of PD-L1 in melanoma cells, and all of them are secreted. Secretion of sPD-L1 resulted from alternate splicing activities, cytokine induction, cell stress, cell injury, and cell death in melanoma cells. Pretreatment levels of sPD-L1 were elevated in stage IV melanoma patient sera compared with healthy donors. High pretreatment levels of sPD-L1 were associated with increased likelihood of progressive disease in patients treated by CTLA-4 or PD-1 blockade. Although changes in circulating sPD-L1 early after treatment could not distinguish responders from those with progressive disease, after five months of treatment by CTLA-4 or PD-1 blockade patients who had increased circulating sPD-L1 had greater likelihood of developing a partial response. Induction of sPD-L1 was associated with increased circulating cytokines after CTLA-4 blockade but not following PD-1 blockade. Circulating sPD-L1 is a prognostic biomarker that may predict outcomes for subgroups of patients receiving checkpoint inhibitors. Cancer Immunol Res; 5(6); 480–92. ©2017 AACR.
Data from Subcellular Localization of Antigen in Keratinocytes Dictates Delivery of CD4+ T-cell Help for the CTL Response upon Therapeutic DNA Vaccination into the Skin
Authors: Bąbała Nikolina , Bovens Astrid , de Vries Evert , Iglesias-Guimarais Victoria , Ahrends Tomasz , Krummel Matthew F. , Borst Jannie , Bins Adriaan D.
Published: March 2024

Abstract
In a mouse model of therapeutic DNA vaccination, we studied how the subcellular localization of vaccine protein impacts antigen delivery to professional antigen-presenting cells and efficiency of CTL priming. Cytosolic, membrane-bound, nuclear, and secretory versions of ZsGreen fluorescent protein, conjugated to MHC class I and II ovalbumin (OVA) epitopes, were expressed in keratinocytes by DNA vaccination into the skin. ZsGreen-OVA versions reached B cells in the skin-draining lymph node (dLN) that proved irrelevant for CTL priming. ZsGreen-OVA versions were also actively transported to the dLN by dendritic cells (DC). In the dLN, vaccine proteins localized to classical (c)DCs of the migratory XCR1+ and XCR− subtypes, and—to a lesser extent—to LN-resident cDCs. Secretory ZsGreen-OVA induced the best antitumor CTL response, even though its delivery to cDCs in the dLN was significantly less efficient than for other vaccine proteins. Secretory ZsGreen-OVA protein proved superior in CTL priming, because it led to in vivo engagement of antigen-loaded XCR1+, but not XCR1−, cDCs. Secretory ZsGreen-OVA also maximally solicited CD4+ T-cell help. The suboptimal CTL response to the other ZsGreen-OVA versions was improved by engaging costimulatory receptor CD27, which mimics CD4+ T-cell help. Thus, in therapeutic DNA vaccination into the skin, mere inclusion of helper epitopes does not ensure delivery of CD4+ T-cell help for the CTL response. Targeting of the vaccine protein to the secretory route of keratinocytes is required to engage XCR1+ cDC and CD4+ T-cell help and thus to promote CTL priming. Cancer Immunol Res; 6(7); 835–47. ©2018 AACR.
Data from NetH2pan: A Computational Tool to Guide MHC Peptide Prediction on Murine Tumors
Authors: DeVette Christa I. , Andreatta Massimo , Bardet Wilfried , Cate Steven J. , Jurtz Vanessa I. , Jackson Kenneth W. , Welm Alana L. , Nielsen Morten , Hildebrand William H.
Published: March 2024

Abstract
With the advancement of personalized cancer immunotherapies, new tools are needed to identify tumor antigens and evaluate T-cell responses in model systems, specifically those that exhibit clinically relevant tumor progression. Key transgenic mouse models of breast cancer are generated and maintained on the FVB genetic background, and one such model is the mouse mammary tumor virus-polyomavirus middle T antigen (MMTV-PyMT) mouse—an immunocompetent transgenic mouse that exhibits spontaneous mammary tumor development and metastasis with high penetrance. Backcrossing the MMTV-PyMT mouse from the FVB strain onto a C57BL/6 genetic background, in order to leverage well-developed C57BL/6 immunologic tools, results in delayed tumor development and variable metastatic phenotypes. Therefore, we initiated characterization of the FVB MHC class I H-2q haplotype to establish useful immunologic tools for evaluating antigen specificity in the murine FVB strain. Our study provides the first detailed molecular and immunoproteomic characterization of the FVB H-2q MHC class I alleles, including >8,500 unique peptide ligands, a multiallele murine MHC peptide prediction tool, and in vivo validation of these data using MMTV-PyMT primary tumors. This work allows researchers to rapidly predict H-2 peptide ligands for immune testing, including, but not limited to, the MMTV-PyMT model for metastatic breast cancer. Cancer Immunol Res; 6(6); 636–44. ©2018 AACR.
Data from CAR-T Cells Surface-Engineered with Drug-Encapsulated Nanoparticles Can Ameliorate Intratumoral T-cell Hypofunction
Authors: Siriwon Natnaree , Kim Yu Jeong , Siegler Elizabeth , Chen Xianhui , Rohrs Jennifer A. , Liu Yarong , Wang Pin
Published: March 2024

Abstract
One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor microenvironment (TME), which inactivates the function of tumor-infiltrating lymphocytes (TIL) through the production of immunosuppressive molecules, such as adenosine. Adenosine inhibits the function of CD4+ and CD8+ T cells by binding to and activating the A2a adenosine receptor (A2aR) expressed on their surface. This suppression pathway can be blocked using the A2aR-specific small molecule antagonist SCH-58261 (SCH), but its applications have been limited owing to difficulties delivering this drug to immune cells within the TME. To overcome this limitation, we used CAR-engineered T cells as active chaperones to deliver SCH-loaded cross-linked, multilamellar liposomal vesicles (cMLV) to tumor-infiltrating T cells deep within the immune suppressive TME. Through in vitro and in vivo studies, we have demonstrated that this system can be used to effectively deliver SCH to the TME. This treatment may prevent or rescue the emergence of hypofunctional CAR-T cells within the TME. Cancer Immunol Res; 6(7); 812–24. ©2018 AACR.
Data from A Synthetic DNA, Multi-Neoantigen Vaccine Drives Predominately MHC Class I CD8+ T-cell Responses, Impacting Tumor Challenge
Authors: Duperret Elizabeth K. , Perales-Puchalt Alfredo , Stoltz Regina , G.H. Hiranjith , Mandloi Nitin , Barlow James , Chaudhuri Amitabha , Sardesai Niranjan Y. , Weiner David B.
Published: March 2024

Abstract
T-cell recognition of cancer neoantigens is important for effective immune-checkpoint blockade therapy, and an increasing interest exists in developing personalized tumor neoantigen vaccines. Previous studies utilizing RNA and long-peptide neoantigen vaccines in preclinical and early-phase clinical studies have shown immune responses predominantly driven by MHC class II CD4+ T cells. Here, we report on a preclinical study utilizing a DNA vaccine platform to target tumor neoantigens. We showed that optimized strings of tumor neoantigens, when delivered by potent electroporation-mediated DNA delivery, were immunogenic and generated predominantly MHC class I–restricted, CD8+ T-cell responses. High MHC class I affinity was associated specifically with immunogenic CD8+ T-cell epitopes. These DNA neoantigen vaccines induced a therapeutic antitumor response in vivo, and neoantigen-specific T cells expanded from immunized mice directly killed tumor cells ex vivo. These data illustrate a unique advantage of this DNA platform to drive CD8+ T-cell immunity for neoantigen immunotherapy.
Data from Soluble CD80 Protein Delays Tumor Growth and Promotes Tumor-Infiltrating Lymphocytes
Authors: Horn Lucas A. , Long Tiha M. , Atkinson Ryan , Clements Virginia , Ostrand-Rosenberg Suzanne
Published: March 2024

Abstract
Tumor cells use various immune-suppressive strategies to overcome antitumor immunity. One such method is tumor expression of programmed death ligand-1 (PD-L1), which triggers apoptotic death or anergy upon binding programmed death-1 (PD-1) on T cells. Our previous in vitro cellular studies with human and mouse PD-L1+ tumor cells demonstrated that a soluble form of the costimulatory molecule CD80 prevented PD-L1–mediated immune suppression and restored T-cell activation by binding PD-L1 and blocking interaction with PD-1. We now report that in vivo treatment of established syngeneic PD-L1+ CT26 colon carcinoma and B16F10 melanoma tumors with CD80-Fc delays tumor growth and promotes tumor-infiltrating T cells. Studies with PD-1−/− and CD28−/− mice demonstrate that soluble CD80 acts in vivo by simultaneously neutralizing PD-1 suppression and activating through CD28. We also report that soluble CD80 mediates its effects by activating transcription factors EGR1-4, NF-κB, and MAPK, downstream signaling components of the CD28 and T-cell receptor pathways. Soluble CD80 binds to CTLA-4 on activated human peripheral blood mononuclear cells. However, increasing quantities of CTLA-4 antagonist antibodies do not increase T-cell activation. These results indicate that soluble CD80 does not suppress T-cell function through CTLA-4 and suggest that CTLA-4 acts as a decoy receptor for CD80, rather than functioning as a suppressive signaling receptor. Collectively, these studies demonstrate that soluble CD80 has therapeutic efficacy in vivo in mouse tumor systems and that its effects are due to its ability to inhibit PD-1–mediated suppression while concurrently activating T cells through CD28. Cancer Immunol Res; 6(1); 59–68. ©2017 AACR.
Data from Enhancement of Peptide Vaccine Immunogenicity by Increasing Lymphatic Drainage and Boosting Serum Stability
Authors: Moynihan Kelly D. , Holden Rebecca L. , Mehta Naveen K. , Wang Chensu , Karver Mark R. , Dinter Jens , Liang Simon , Abraham Wuhbet , Melo Mariane B. , Zhang Angela Q. , Li Na , Gall Sylvie Le , Pentelute Bradley L. , Irvine Darrell J.
Published: March 2024

Abstract
Antitumor T-cell responses have the potential to be curative in cancer patients, but the induction of potent T-cell immunity through vaccination remains a largely unmet goal of immunotherapy. We previously reported that the immunogenicity of peptide vaccines could be increased by maximizing delivery to lymph nodes (LNs), where T-cell responses are generated. This was achieved by conjugating the peptide to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-PEG (DSPE-PEG) to promote albumin binding, which resulted in enhanced lymphatic drainage and improved T-cell responses. Here, we expanded upon these findings and mechanistically dissected the properties that contribute to the potency of this amphiphile-vaccine (amph-vaccine). We found that multiple linkage chemistries could be used to link peptides with DSPE-PEG, and further, that multiple albumin-binding moieties conjugated to peptide antigens enhanced LN accumulation and subsequent T-cell priming. In addition to enhancing lymphatic trafficking, DSPE-PEG conjugation increased the stability of peptides in serum. DSPE-PEG peptides trafficked beyond immediate draining LNs to reach distal nodes, with antigen presented for at least a week in vivo, whereas soluble peptide presentation quickly decayed. Responses to amph-vaccines were not altered in mice deficient in the albumin-binding neonatal Fc receptor (FcRn), but required Batf3-dependent dendritic cells (DCs). Amph-peptides were processed by human DCs equivalently to unmodified peptides. These data define design criteria for enhancing the immunogenicity of molecular vaccines to guide the design of next-generation peptide vaccines. Cancer Immunol Res; 6(9); 1025–38. ©2018 AACR.
Data from Antagonism of IAPs Enhances CAR T-cell Efficacy
Authors: Michie Jessica , Beavis Paul A. , Freeman Andrew J. , Vervoort Stephin J. , Ramsbottom Kelly M. , Narasimhan Vignesh , Lelliott Emily J. , Lalaoui Najoua , Ramsay Robert G. , Johnstone Ricky W. , Silke John , Darcy Phillip K. , Voskoboinik Ilia , Kearney Conor J. , Oliaro Jane
Published: March 2024

Abstract
Chimeric antigen receptor (CAR) T-cell therapy has proven successful in the treatment of hematological malignancies, notably acute lymphoblastic leukemia and B-cell lymphoma. However, the efficacy of CAR T cells against solid tumors is poor, likely due to tumor-associated immunosuppression. Here, we demonstrated that antagonizing the “inhibitor of apoptosis proteins” with the clinical smac-mimetic, birinapant, significantly enhanced the antitumor activity of CAR T cells in a tumor necrosis factor (TNF)-dependent manner. Enhanced tumor cell death occurred independently of the perforin-mediated granule exocytosis pathway, underscoring the cytotoxic potential of CAR T-cell–derived TNF. Combining CAR T-cell therapy with birinapant significantly reduced established tumor growth in vivo, where either therapy alone was relatively ineffective. Using patient biopsy-derived tumoroids, we demonstrated the synergistic potential of combining CAR T-cell therapy with smac-mimetics. Taken together, we identified CAR T-cell–derived TNF as a potent antitumor effector, which can be further harnessed by smac-mimetics.
Data from Wnt3a Neutralization Enhances T-cell Responses through Indirect Mechanisms and Restrains Tumor Growth
Authors: Pacella Ilenia , Cammarata Ilenia , Focaccetti Chiara , Miacci Stefano , Gulino Alessandro , Tripodo Claudio , Ravà Micol , Barnaba Vincenzo , Piconese Silvia
Published: March 2024

Abstract
The Wnt/β-catenin pathway regulates T-cell functions, including the repression of effector functions to the advantage of memory development via Tcf1. In a companion study, we demonstrate that, in human cancers, Wnt3a/β-catenin signaling maintains tumor-infiltrating T cells in a partially exhausted status. Here, we have investigated the effects of Wnt3a neutralization in vivo in a mouse tumor model. Abundant Wnt3a was released, mostly by stromal cells, in the tumor microenvironment. We tested whether Wnt3a neutralization in vivo could rescue the effector capacity of tumor-infiltrating T cells, by administering an antibody to Wnt3a to tumor-bearing mice. This therapy restrained tumor growth and favored the expansion of tumor antigen–specific CD8+ effector memory T cells with increased expression of Tbet and IFNγ and reduced expression of Tcf1. However, the effect was not attributable to the interruption of T-cell–intrinsic β-catenin signaling, because Wnt3a/β-catenin activation correlated with enhanced, not reduced, T-cell effector functions both ex vivo and in vitro. Adoptively transferred CD8+ T cells, not directly exposed to the anti-Wnt3a antibody but infiltrating previously Wnt3a-neutralized tumors, also showed improved functions. The rescue of T-cell response was thus secondary to T-cell–extrinsic changes that likely involved dendritic cells. Indeed, tumor-derived Wnt3a strongly suppressed dendritic cell maturation in vitro, and anti-Wnt3a treatment rescued dendritic cell activities in vivo. Our results clarify the function of the Wnt3a/β-catenin pathway in antitumor effector T cells and suggest that Wnt3a neutralization might be a promising immunotherapy for rescuing dendritic cell activities. Cancer Immunol Res; 6(8); 953–64. ©2018 AACR.
Data from Allelic Polymorphisms of KIRs and HLAs Predict Favorable Responses to Tyrosine Kinase Inhibitors in CML
Authors: Ureshino Hiroshi , Shindo Takero , Kojima Hiroto , Kusunoki Yasushi , Miyazaki Yuki , Tanaka Hidenori , Saji Hiroh , Kawaguchi Atsushi , Kimura Shinya
Published: March 2024

Abstract
Response to tyrosine kinase inhibitors (TKIs) is variable in chronic myeloid leukemia (CML), and elevated natural killer (NK) cells during TKI therapy are positively correlated with superior outcomes. NK cell function involves interactions of their killer immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I on target cells, and the avidity of KIR–HLA interactions depends on the combination of KIR and HLA alleles. We hypothesized that KIR and HLA polymorphisms may influence response to TKIs. KIR and HLA allele genotyping was performed by next-generation sequencing for 76 CML cases, and association with clinical outcome was analyzed. Second-generation TKIs as first-line therapy and patients' sex (female) were strongly associated with achievement of complete molecular response (CMR: MR4.0) after 2 years (P < 0.001 and P = 0.002, respectively). After adjustment for these two characteristics, several KIR alleles remained associated with achievement of MR4.0: KIR2DL4*005/011 or *008 (HR = 1.797, P = 0.032); KIR2DS4*003 or *007/010 (HR = 3.348, P < 0.001); KIR3DL1*005 (HR = 2.746, P = 0.003); and KIR3DL2*009 or *010 [HR = 1.980 (1.109–3.524), P = 0.021]. Strong linkage among these alleles exists, implying that they comprise favorable KIR allele haplotypes. Allelic polymorphisms of KIR3DL1 and HLA-B determine their differential avidity into strong/weak or no interaction. Patients carrying noninteracting KIR3DL1 and HLA-B allele pairs achieved better outcomes than those with strongly interacting pairs, and KIR3DL1*005 associated with a positive outcome among patients with weak-interacting pairs. Thus, KIR3DL1*005 and its associated haplotypes associated with superior TKI therapeutic effects. The combinations of these KIR and HLA alleles may correlate with potent NK cell immunity against CML. Cancer Immunol Res; 6(6); 745–54. ©2018 AACR.
Data from CD16+NKG2Ahigh Natural Killer Cells Infiltrate Breast Cancer–Draining Lymph Nodes
Authors: Frazao Alexandra , Messaoudene Meriem , Nunez Nicolas , Dulphy Nicolas , Roussin France , Sedlik Christine , Zitvogel Laurence , Piaggio Eliane , Toubert Antoine , Caignard Anne
Published: March 2024

Abstract
Tumor-draining lymph nodes (TD-LNs) are the first site of metastasis of breast cancer. Natural killer (NK) cells that infiltrate TD-LNs [including noninvaded (NI) or metastatic (M)-LNs from breast cancer patients] and NK cells from healthy donor (HD)-LNs were characterized, and their phenotype analyzed by flow cytometry. Low percentages of tumor cells invaded M-LNs, and these cells expressed ULBP2 and HLA class I molecules. Although NK cells from paired NI and M-LNs were similar, they expressed different markers compared with HD-LN NK cells. Compared with HD-LNs, TD-LN NK cells expressed activating DNAM-1, NKG2C and inhibitory NKG2A receptors, and exhibited elevated CXCR3 expression. CD16, NKG2A, and NKp46 expression were shown to be increased in stage IIIA breast cancer patients. TD-LNs contained a large proportion of activated CD56brightCD16+ NK cells with high expression of NKG2A. We also showed that a subset of LN NK cells expressed PD-1, expression of which was correlated with NKp30 and NKG2C expression. LN NK cell activation status was evaluated by degranulation potential and lytic capacity toward breast cancer cells. NK cells from TD-LNs degranulated after coculture with breast cancer cell lines. Cytokine-activated TD-LN NK cells exerted greater lysis of breast cancer cell lines than HD-LN NK cells and preferentially lysed the HLA class Ilow MCF-7 breast cancer cell line. TD-LNs from breast cancer patients, thus, contained activated lytic NK cells. The expression of inhibitory receptor NKG2A and checkpoint PD-1 by NK cells infiltrating breast cancer–draining LNs supports their potential as targets for immunotherapies using anti-NKG2A and/or anti–PD-1.
Data from Endoplasmic Reticulum Stress Contributes to Mitochondrial Exhaustion of CD8+ T Cells
Authors: Hurst Katie E. , Lawrence Kiley A. , Essman Matthew T. , Walton Zeke J. , Leddy Lee R. , Thaxton Jessica E.
Published: March 2024

Abstract
Tumor antigen–specific T cells rapidly lose energy and effector function in tumors. The cellular mechanisms by which energy loss and inhibition of effector function occur in tumor-infiltrating lymphocytes (TILs) are ill-defined, and methods to identify tumor antigen–specific TILs that experience such stress are unknown. Processes upstream of the mitochondria guide cell-intrinsic energy depletion. We hypothesized that a mechanism of T-cell–intrinsic energy consumption was the process of oxidative protein folding and disulfide bond formation that takes place in the endoplasmic reticulum (ER) guided by protein kinase R-like endoplasmic reticulum kinase (PERK) and downstream PERK axis target ER oxidoreductase 1 (ERO1α). To test this hypothesis, we created TCR transgenic mice with a T-cell–specific PERK gene deletion (OT1+Lckcre+PERKf/f, PERK KO). We found that PERK KO and T cells that were pharmacologically inhibited by PERK or ERO1α maintained reserve energy and exhibited a protein profile consistent with reduced oxidative stress. These T-cell groups displayed superior tumor control compared with T effectors. We identified a biomarker of ER-induced mitochondrial exhaustion in T cells as mitochondrial reactive oxygen species (mtROS), and found that PD-1+ tumor antigen–specific CD8+ TILs express mtROS. In vivo treatment with a PERK inhibitor abrogated mtROS in PD-1+ CD8+ TILs and bolstered CD8+ TIL viability. Combination therapy enabled 100% survival and 71% tumor clearance in a sarcoma mouse model. Our data identify the ER as a regulator of T-cell energetics and indicate that ER elements are effective targets to improve cancer immunotherapy.
Treatable Traits in Pregnant Women with Asthma
Authors: Ramlal Meera , Van der Meer Renske , Bendien Sarah
Published: March 2024

Background: Asthma is the most common chronic respiratory disease in pregnancy, affecting approximately 8–10% of pregnant women. Uncontrolled asthma is associated with adverse perinatal outcomes, including low birth weight, preterm birth, and maternal complications such as pre-eclampsia. Summary: A current approach to the management of chronic airway diseases is based on targeting treatable traits. The aim of this review was to define treatable traits in pregnant women with asthma based on recent literature and to determine personalized treatment options according to these traits. Traits addressed in this review that may improve asthma control and pregnancy outcomes are fractional exhaled nitric oxide-based asthma monitoring and treatment, medication adherence and inhalation technique, impaired lung function, smoking cessation and comorbidity including psychological conditions (depression and anxiety), obesity, rhinitis, gastroesophageal reflux disease, chronic rhinosinusitis with or without nasal polyps, and sleep apnea. Key Messages: All the treatable traits discussed have the potential to improve asthma control and pregnancy outcomes in pregnant women with asthma. Further research is needed to determine which management approaches are best to improve asthma control during pregnancy, to identify other relevant treatable traits, and to determine whether the treatable trait approach is feasible and beneficial in pregnant women with asthma.
Effect of Renin-Angiotensin System Blockers in Acute Myocardial Infarction Patients with Acute Kidney Injury
Authors: Kim Kyung An , Lee Joo Eun , Choi Ik Jun , Lee Kwan Yong , Kim Chan Joon , Park Mahn-Won , Park Chul Soo , Kim Hee-Yeol , Yoo Ki-Dong , Jeon Doo Soo , Jeong Myung Ho , Chang Kiyuk
Published: March 2024

Background: Renin-angiotensin system blockers (RASBs) are known to improve mortality after acute myocardial infarction (AMI). However, there remain uncertainties regarding treatment with RASBs after AMI in patients with renal dysfunction, and especially in the setting of acute kidney injury (AKI).
Methods: Patients from a multicenter AMI registry undergoing percutaneous coronary intervention in Korea were stratified and analyzed according to the presence of AKI, defined as an increase in serum creatinine levels of ≥ 0.3mg/dL or ≥ 50% increase from baseline during admission, and RASB prescription at discharge. The primary outcome of interest was 5-year all-cause mortality.
Results: In total 9,629 patients were selected for initial analysis, of which 2,405 had an episode of AKI. After adjustment using multivariable Cox regression, treatment with RASBs at discharge was associated with decreased all-cause mortality in the entire cohort (HR 0.849, CI 0.753-0.956), but not for the patients with AKI (HR 0.988, CI 0.808-1.208). In subgroup analysis, RASBs reduced all-cause mortality in patients with stage I AKI (HR 0.760, CI 0.584-0.989) but not for stage II and III AKI (HR 1.200, CI 0.899-1.601, interaction p-value 0.002). Similar heterogeneities between RASB use and AKI severity were also observed for other clinical outcomes of interest.
Conclusion: Treatment with RASBs in patients with AMI and concomitant AKI is associated with favorable outcomes in non-severe AKI, but not in severe AKI. Further studies to confirm these results and to develop strategies to minimize the occurrence of adverse effects arising from RASB treatment are needed.
The Effect of Mind-Body Intervention on Lymphocyte Doubling Time and Treatment-Free Survival in Treatment-Naïve Chronic Lymphocytic Leukemia Patients
Authors: Shapira Shirley , Hirschberger Naama , Ofran Yishai , Mizrahi Barak , Mandel Esti , Benjamini Ohad , Rabinowicz Noa , Zoref-Lorenz Adi
Published: March 2024

Introduction: Mind-body intervention (MBI) serves as a supportive aid in oncology. We hypothesized that MBI could impact the progression of chronic lymphocytic leukemia (CLL) in the “watch and wait” (w&w) phase. Methods: We conducted a non-randomized, prospective controlled study between the years 2020 and 2022 on 76 treatment-naïve CLL patients in the w&w phase. Thirty-seven patients were included in the intervention arm and received MBI, while 39 patients were included in the control group. The primary and secondary endpoints were prolongation of lymphocyte doubling time (LDT) and treatment-free survival (TFS). LDT was compared at 0, 180, 360, and 540 days using paired t tests. TFS was compared between the intervention and control groups using the log-rank test. Cox proportional hazards models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) for TFS in the intervention group compared to the control, stratified by the study covariates. Results: MBI prolonged LDT at all time points, including at day 360 (median of 2.47 years; CI 1.05–3.9; p = 0.001). TFS at 18 months was longer in the intervention group compared to the control group (HR 0.23; CI 0.06–0.79, p = 0.01). Conclusions: MBI was associated with prolonged LDT and TFS in patients with CLL in the w&w phase. These results provide a basis for a larger randomized controlled trial.
Diagnostic Yield of Exome Sequencing in Early-Onset Hypertensive Nephropathy in Adults
Authors: Serre Justine , Doreille Alice , Raymond Laure , Suc Gaspard , Bobot Mickaël , Dancer Marine , Rafat Cédric , Mesnard Laurent
Published: March 2024

Introduction: Hypertensive nephrosclerosis (HN) ranks as one of the most frequent causes of chronic kidney disease (CKD), but its very existence has repeatedly been called into question, especially in young adults. Its diagnostic framework is established chiefly on non-specific clinical criteria, and its defining histopathological set of features is in fact shared by numerous other conditions. Genetic testing based on exome sequencing (ES) has emerged as a comprehensive tool to detect Mendelian diseases in timely fashion in nephrology, with a significant number of re-established diagnoses. The aim of this study was to investigate the diagnostic yield of ES in patients with a clinical diagnosis of hypertensive nephropathy. Method: Since September 2018, ES has been readily available as part of the routine diagnostic work-up in our institution. The indication of ES includes hypertensive nephropathy of early onset (i.e., <45 years old). We retrospectively collected the ES data performed in the context of hypertensive nephropathy in our institution between September 2018 and February 2021. Results: A total of 128 patients were sequenced in the context of hypertensive nephropathy with early onset. The chief indications of ES were an early onset of CKD (47%), family history of kidney disease (8%), or both (18%). We detected diagnostic variants in 19 of the 128 patients (15%), encompassing a total of 13 different monogenic disorders. The diagnostic yield of ES was lower in patients of African ancestry (diagnostic yield of 7 vs. 30% in non-African ancestry patients, p < 0.001). Conclusions: The high diagnostic yield of ES (15%) in a population of patients thought to have HN casts further doubts on the validity of the existing diagnosis criteria, including histological criteria, supposed to characterize the condition. This was especially true in patients with no African ancestry, where ES positivity reached 30%.
Quick guide to evolutionary medicine in neuroimmunomodulation: Why “evolved for the benefit of the species” is not a valid argument
Authors: Schradin Carsten , Jaeggi Adrian V. , Criscuolo Francois
Published: March 2024

Evolutionary medicine builds on evolutionary biology and explains why natural selection has left us vulnerable to disease. Unfortunately, several misunderstandings exist in the medical literature about the levels and mechanisms of evolution. Reasons for these problems start from the lack of teaching evolutionary biology in medical schools. A common mistake is to assume that “traits must benefit the species, as otherwise the species would have gone extinct in the past”, confusing evolutionary history (phylogeny) with evolutionary function (fitness). Here we summarize some basic aspects of evolutionary medicine by pointing out: 1. Evolution has no aim. 2. For adaptive evolution to occur, a trait does not have to be beneficial to its carrier throughout its entire life. 3. Not every single individual carrying an adaptive trait needs to have higher than average fitness. 4. Traits do not evolve for the benefit of the species. Using examples from the field of neuroimmunomodulation like sickness behaviour (nervous system), testosterone (hormones), and cytokines (immunity), we show how misconceptions arise from not differentiating between the explanatory categories of phylogeny (evolutionary history) and evolutionary function (fitness).