Journal for Immunotherapy of Cancer最新文献

{"title":"Ectopic expression of GDF15 in cancer-associated fibroblasts enhances melanoma immunosuppression via the GFRAL/RET cascade.","authors":"Zhijie Zhao, Huabao Cai, Wenyang Nie, Xiaojing Wang, Zhenzhen Zhao, Fu Zhao, Yisheng Chen, Zhiwen Luo, Zhiheng Lin, Li Lin, Yantao Ding","doi":"10.1136/jitc-2024-011036","DOIUrl":"10.1136/jitc-2024-011036","url":null,"abstract":"<p><strong>Background: </strong>A key aspect of tumor biology is the involvement of cancer-associated fibroblasts (CAFs) in shaping the immunosuppressive microenvironment. However, the dynamic and complex key roles of CAFs in the melanoma immune microenvironment have not been elucidated.</p><p><strong>Methods: </strong>The CAFs landscape in melanoma was characterized using single-cell RNA-seq and spatial transcriptomics. Molecular dynamics simulations were employed to validate the interactions between CAFs and melanoma cells. Bulk RNA-seq was used to establish a prognostic model. To validate the expression of key targets, western blotting, quantitative real-time PCR, and ELISA were performed. The molecular interactions were confirmed via co-immunoprecipitation, chromatin immunoprecipitation, and luciferase gene reporter assays. In-depth molecular mechanisms were explored using lentiviral transfection, cell co-culture experiments, recombinant protein rescue experiments, flow cytometry, knockout mice, and Cre-loxP system mice.</p><p><strong>Results: </strong>This study identified a unique group of CAFs expressing high levels of growth differentiation factor 15 (GDF15). The paracrine secretion of GDF15 was regulated by the transcription factor FOXP1, which subsequently binds to the TGFBR2 receptor on melanoma cells, driving their proliferation and metastatic capacity. In addition, CAFs-derived GDF15 interacts with the GFRAL receptor on melanoma cells, thereby promoting RET phosphorylation and triggering downstream signaling axes, inducing increased tumor cell stemness and secretion of inflammatory factors CCL18 and TGF-β. This cascade reaction ultimately induces macrophage polarization to the immunosuppressive M2 phenotype, assists in the establishment of an immunosuppressive microenvironment, and leads to accelerated melanoma lung metastasis.</p><p><strong>Conclusion: </strong>By integrating single-cell RNA-seq, spatial transcriptomics, bulk RNA-seq, molecular dynamics simulation and complete experimental design, this study comprehensively characterized that ectopic expression of CAFs-derived GDF15 can act as an accomplice in melanoma progression by inducing increased tumor cell stemness and macrophage M2 polarization, reshaping the immune landscape of melanoma, and providing new ideas and new targets for precision immunotherapy of melanoma.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potentiation of cancer immunogenicity by targeting PARP.","authors":"Dominik Humer, Victoria Klepsch, Gottfried Baier","doi":"10.1136/jitc-2024-011056","DOIUrl":"10.1136/jitc-2024-011056","url":null,"abstract":"<p><p>A team of scientists led by Quigley Goa demonstrates that Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi) can induce tumor cell death in a manner that allows immune cells to better recognize and attack the tumor. Specifically, PARPi are approved for the treatment of tumors with homologous recombination repair defects. Due to their pre-existing DNA repair defects, PAPRi appear to be a pharmacological tool to induce immunogenic cell death (ICD). Remarkably, therefore, both increased tumor neoantigen generation and reprogramming of the tumor immune microenvironment to an immunostimulatory state antagonize impending immunosuppression and consequently promote enhanced antitumor immunity. This finding strongly supports PARPi targeting as a promising approach to alleviate intratumoral effector T cell immune dysfunction, particularly in the context of immunotherapy resistance. In conclusion, this well-defined relationship between PARPi-based chemotherapy and ICD of tumor cells may offer substantial potential as a valuable sensitizer for future combinatorial cancer immunotherapy, which together with immune checkpoint therapy, but potentially also with others including cancer vaccines, is likely to be more effective against defined solid tumors and better promote host-protective cancer immune control (see related article by Xia <i>et al</i>, 2024).</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198780/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484449","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bystander CAR^-CD8⁺ T cells in a CAR-T cell product can expand and enhance the antitumor effects of a bispecific antibody.","authors":"Junichi Kato, Tatsuya Konishi, Takatsugu Honda, Masaki Maruta, Shogo Nabe, Yuya Masuda, Meika Matsumoto, Natsumi Kawasaki, Yukihiro Miyazaki, Yasukazu Doi, Yasunori Takasuka, Jun Yamanouchi, Toshiki Ochi, Katsuto Takenaka","doi":"10.1136/jitc-2025-011690","DOIUrl":"10.1136/jitc-2025-011690","url":null,"abstract":"<p><p>Although bispecific antibody (BsAb) treatment is a valuable therapeutic option for post chimeric antigen receptor (CAR)-T cell therapy against relapsed/refractory large B-cell lymphoma, it remains to be clarified why it is still effective after intensive T-cell redirection therapy. Recently, the therapeutic potential of bystander CD8⁺ T cells in the field of cancer immunotherapy have been discussed. In this study, we have shown a clinical impact where bystander CAR-negative CD8⁺ T cells from a CAR-T cell product have a potential to augment immune responses of BsAb therapy through a case with relapsed diffuse large B-cell lymphoma after CD19 CAR-T cell therapy. T cells in a CAR-T-cell product dominantly showed central and effector memory T cells, and such T-cell phenotypes in peripheral blood significantly increased after CAR-T cell therapy. Furthermore, chronological T-cell receptor-β repertoire analyses for both CD8⁺ T cells and CD4⁺ T cells suggested that product-derived bystander CAR^-CD8⁺ T cells successfully existed in a relapsed lymph node and expanded in the body after BsAb therapy. Further analyses are necessary, but our findings might help to explain the mechanisms and benefits of this sequential approach and strengthen the sequence of CAR-T cell therapy prior to BsAb therapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12198839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144484446","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Attenuated immune surveillance during squamous cell transformation of pancreatic adenosquamous cancer defines new therapeutic opportunity for cancer interception.","authors":"Xinyuan Chen, Shanyue Sun, Shuofeng Li, Shuangni Yu, Jie Chen, Xianlong Chen","doi":"10.1136/jitc-2025-012066","DOIUrl":"10.1136/jitc-2025-012066","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Pancreatic adenosquamous cancer (PASC) is an extremely rare subtype of pancreatic cancer characterized by a poorer prognosis and higher likelihood of metastasis compared with the more prevalent pancreatic ductal adenocarcinoma (PDAC). Although genomic changes during PASC tumorigenesis have been documented, the corresponding alterations in the tumor immune microenvironment (TIME) remain inadequately elucidated. Therefore, this study aims to analyze the immune landscape of PASC by employing multiplex immunohistochemistry (mIHC) and digital image analysis.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;In this study, we analyzed four independent cohorts comprising 120 patients with PASC and 386 patients with PDAC. We employed mIHC to quantify three in situ panels of immuno-oncology-related biomarkers at subcellular resolution. We then used five samples to perform laser capture microdissection, RNA sequencing, and whole-exome sequencing to explore the underlying mechanisms of the compartment-specific immune phenotypes in PASC.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Our findings revealed a more immunosuppressive TIME in PASC compared with PDAC, characterized by a decreased abundance of T cells. Immune cell types indicative of enhanced immune surveillance, including cytotoxic and memory T cells and antigen-experienced T cells, were present at significantly lower densities in PASC compared with PDAC. Conversely, some immunosuppressive macrophage phenotypes exhibited increased distribution in PASC. Immunosuppressive immune cells (ICs) were abundant, enriched within stromal regions, highly heterogeneous across tumors, and exhibited distinct distributions between squamous cell (SQC) and adenocarcinoma (ADC) compartments in PASC. Notably, the TIME of SQC compartments harbored more exhausted T cells compared with synchronous ADC compartments, indicating attenuated immune surveillance during squamous transformation. Transcriptomic profiling of microdissected SQC and ADC regions revealed immune exhaustion signatures and downregulated T-cell differentiation pathways in SQC compartments, alongside altered antigen presentation machinery and elevated tumor mutational burden, suggesting squamous-specific tumor-associated antigens with potential immunotherapeutic relevance. Beyond differences in IC density, we observed closer spatial proximity of CD45RO&lt;sup&gt;+&lt;/sup&gt; and PD-1&lt;sup&gt;+&lt;/sup&gt;CD3&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt; T cells to tumor cells within 10, 20 and 30 µm ranges in PASC compared with PDAC, with variations by histological subregion. Furthermore, we found distinct expression patterns of the programmed cell death protein-1 (PD-1)/programmed death ligand 1 (PD-L1) and T-cell immunoreceptor with immunoglobulin and the ITIM domain (TIGIT)/CD155 axes in the PASC TIME associated with survival outcomes. Notably, TIGIT&lt;sup&gt;+&lt;/sup&gt;CD8&lt;sup&gt;+&lt;/sup&gt; T cells and CD155&lt;sup&gt;+&lt;/sup&gt; CD68&lt;sup&gt;+&lt;/sup&gt;macrophages, along with their proximity to tumor cells, served as inde","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186043/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Serotonin receptor 5-HT_2A as a potential target for HCC immunotherapy.","authors":"Rong En Tay, Charmaine Min Ho, Nicholas Da Zhi Ang, Hui Chien Tay, Daniel Z Lopez, Qiao Rui Na, Yi Wen Tan, Ser Mei Koh, Kim Peng Tan, Wendy Lee, Jackwee Lim, Maichan Lau, Han Chong Toh, Olaf Rotzschke, Laurent Rénia","doi":"10.1136/jitc-2024-011088","DOIUrl":"10.1136/jitc-2024-011088","url":null,"abstract":"<p><strong>Background: </strong>While recent clinical trials of combination immunotherapies for hepatocellular carcinoma (HCC) have shown promising clinical efficacy and survival improvements breakthroughs, there is still much room for further improvement. A key limiting factor for HCC immunotherapy is the intrinsic immunosuppression within the liver microenvironment, resulting in suboptimal priming of tumor-specific CD8 cytotoxic T cells and thus immune evasion by the tumor. Hence, identifying new key molecular pathways suppressing T-cell responses within the liver is critical for the rational design of more effective combination immunotherapies for HCC.</p><p><strong>Methods: </strong>We identified the 5-HT_2A serotonin receptor as a potential target for HCC immunotherapy in a chemical screening approach and validated that targeting 5-HT_2A signaling could be a viable approach for HCC immunotherapy via in vitro and in vivo studies.</p><p><strong>Results: </strong>Disruption of 5-HT_2A signaling using either a selective antagonist small molecule, ketanserin, or by knockout of its coding gene <i>Htr2a</i> augments the cytotoxic effector phenotype of mouse CD8 T cells activated in vitro with immunosuppressive liver non-parenchymal cells. Ketanserin treatment of in vitro activated human CD8 T cells also increased expression of the cytotoxic effector molecules granzyme B and perforin. Abrogation of 5-HT_2A signaling was associated with increased expression of cytotoxicity-related genes such as granzyme B and reduced expression of transcription factors downstream of MAP kinase signaling. In vivo, systemic ketanserin treatment significantly prolonged survival of HCC tumor-bearing mice and was non-inferior to α-programmed death ligand 1 (PD-L1)+α-vascular endothelial growth factor A (VEGFA) combination antibody treatment. Combining ketanserin with αPD-L1+αVEGFA antibodies also significantly prolonged survival relative to control-treated mice while preserving the occurrence of complete tumor regression observed with αPD-L1+αVEGFA treatment alone.</p><p><strong>Conclusions: </strong>Together, our data describe a role for 5-HT_2A as a negative regulator of the cytotoxic effector phenotype in CD8 T cells and highlight the therapeutic potential of targeting 5-HT_2A for HCC immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>Piezo1</i> deletion enhances cross-priming of CD8+ T cells by tumor-infiltrating CD11b+ dendritic cells.","authors":"Melissa Bonner, David Askew, Vrishabhadev Sathish Kumar, Suzanne L Tomchuck, Saada Eid, Muta Abiff, Jay T Myers, Phuong Nguyen, Justin W A Garyu, Tyler E Miller, Alex Yee-Chen Huang","doi":"10.1136/jitc-2025-011815","DOIUrl":"10.1136/jitc-2025-011815","url":null,"abstract":"<p><strong>Background: </strong>Tumor-associated myeloid cells (TAMCs) are an abundant, phenotypically plastic cell population that is critical for initiating a robust antitumor response. To properly combat cancer cells, TAMCs must sense and transduce both soluble and vital biophysical cues imparted by the dense extracellular matrix (ECM) of the tumor microenvironment (TME). Despite ample research enumerating the deleterious effects of a primary tumor's ECM on TAMCs' functionality, few studies have evaluated the contribution of mechanosensitive cation channel(s) underlying these detrimental changes.</p><p><strong>Methods: </strong>Our study aimed to evaluate the significance of the mechanosensitive cation channel PIEZO1 in TAMCs' phenotype and effector functionality. To do so, we generated CD11b-conditional <i>Piezo1</i> knockout mice, orthotopically inoculated them with rhabdomyosarcoma 76-9, an aggressive syngeneic rhabdomyosarcoma cell line, and evaluated tumor burden, pan-immune compartment changes, and intrinsic myeloid and lymphoid transcriptomic and functional changes.</p><p><strong>Results: </strong>Genetic deletion of <i>Piezo1</i> in CD11b-expressing cells significantly hindered primary and metastatic tumor burden. Intratumorally, we observe enhanced infiltration of CD11b+ dendritic cells (DCs) and CD8+, but not CD4+, T cells. This phenotype was driven by CD11b+ DCs that have undergone transcriptional changes related to improved antigen presentation and T cell activation. Despite being canonically inefficient cross-presenters in the wildtype state, <i>Piezo1</i> KO CD11b+ DCs, specifically the cDC2A subpopulation, efficiently cross-prime CD8+ T cells on exposure to exogenous particulate antigens.</p><p><strong>Conclusions: </strong>Here, we report for the first time an association between mechanosensation and cross-presentation by cDC2A cells. Our findings may be impactful to improving the continued development of DC vaccines whose success hinges on proper antigen processing and presentation to cytotoxic T cells in the TME.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hypoxia upregulates the expression of PD-L1 via NPM1 in breast cancer.","authors":"Yihui Yu, Ran Sun, Feiyun Hu, Zite Ding, Xin Li, Jiyuan Han, Leiting Liang, Tian Wang, Guifu Xi, Xueyi Dong, Yanlei Li, Xiulan Zhao, Danfang Zhang","doi":"10.1136/jitc-2024-010151","DOIUrl":"10.1136/jitc-2024-010151","url":null,"abstract":"<p><strong>Background: </strong>A hypoxic microenvironment is the most frequent characteristic in tumor microenvironment. Programmed death-ligand 1 (PD-L1) is an important molecule and therapeutic target that mediates the immune response of tumor cells. Previous studies have shown that hypoxia can lead to increased expression of Nucleophosmin 1 (NPM1) and PD-L1. However, the exact regulatory mechanisms of NPM1 and PD-L1 expression under hypoxic conditions are still poorly understood.</p><p><strong>Methods: </strong>The relationships among hypoxia, NPM1 and PD-L1 were explored by western blotting, immunofluorescence staining, flow cytometry and chromatin immunoprecipitation-quantitativePCR(ChIP-qPCR). Animal tumor models were established to explore the effect of NPM1 expression on tumor growth. The relationships between NPM1 and breast cancer (BC) clinical features and immune infiltration were revealed by bioinformatics analysis.</p><p><strong>Results: </strong>NPM1 mediates increased PD-L1 expression in the hypoxic microenvironment of BC. HIF-1α can increase the expression of NPM1 by activating the p-AKT pathway and binding to the NPM1 promoter. Increased expression of NPM1 can promote tumor growth and inhibit T cell infiltration. Bioinformatics analysis showed that the high expression of NPM1 was associated with poorer survival and immunosuppression in patients with BC.</p><p><strong>Conclusions: </strong>The hypoxic microenvironment promotes PD-L1 expression via NPM1 in BC, which may be further associated with the inhibition of tumor immunity. NPM1 may serve as a potential target for modulating PD-L1 immunotherapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12186055/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475333","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SITC perspective: leveraging patient enrichment biomarkers to accelerate early phase IO drug development.","authors":"Leisha A Emens, Christine Moussion, Patrick Hwu, James L Gulley, Pamela S Ohashi, Carlo B Bifulco, David Feltquate","doi":"10.1136/jitc-2024-010739","DOIUrl":"10.1136/jitc-2024-010739","url":null,"abstract":"<p><p>Cancer immunotherapy (IO) enables patients to live well with cancer for many years, or even be cured. Several investigational IO agents recently failed in early-phase or late-phase trials, leading some to doubt the future of IO. Patient heterogeneity (eg, tumor characteristics, treatment history) increases the risk that a clinically active IO drug might be discarded. Enriching enrollment for patients with biomarkers hypothesized to reflect a higher probability of clinical benefit across clinical development should mitigate this risk. The Society for Immunotherapy of Cancer convened diverse IO stakeholders to discuss leveraging biomarkers at the earliest stages of drug development to accelerate the delivery of innovative IO agents to patients. This group developed a framework based on a biomarker-based enrichment strategy in early trials that evolves into the development of more precise predictive biomarkers in late phase trials. This framework integrates mechanistic insights related to the drug and its impact on the tumor microenvironment derived from preclinical data, digital pathology, exploratory multiomics, and artificial intelligence that are continuously refined through both adaptive and randomized clinical trials. Biomarker-based enrichment in early clinical development should de-risk late-stage trials, ultimately expanding the portfolio of innovative IO drugs available to patients.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12184391/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475345","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer immunotherapy clinical trials to support urgently needed access in low- and middle-income countries: a report from the SITC global access and impact committee.","authors":"Jennifer Dent, Micaella Jorge, Nora Sobrevilla, Thomas S Uldrick, Innocent Adoubi, Jyoti Bajpai, Mauricio Burotto, Huwaida Bulhan, Gideon T Dosunmu, Lilian Ekpo, Satish Gopal, Manuel R Espinoza-Gutarra, N'da Marcelin Homian, T Peter Kingham, Clarissa Mathias, Wilfred Ngwa, Nixon Niyonzima, Blaise Nkegoum, Olufunmilayo I Olopade, Thomas A Odeny, Avery D Posey, Solmaz Sahebjam, Regina Switzer, Ahmad A Tarhini, Verna Vanderpuye, David R Kaufman","doi":"10.1136/jitc-2024-011258","DOIUrl":"10.1136/jitc-2024-011258","url":null,"abstract":"<p><p>Cancer is rapidly on the rise as a cause of morbidity and mortality in low- and middle-income countries (LMICs). However, despite the increasing importance of immune checkpoint inhibitors (ICIs) as a pillar of cancer therapy, access in these settings lags well behind that in high-income countries (HICs). Increasing the evaluation of ICIs through local clinical trials and demonstration projects, and inclusion in multinational clinical trials is the first step to improving access. In particular, the epidemiology and clinical presentation of cancer in LMICs is often distinct from that in HICs, and the impact of immune checkpoint blockade in these settings is understudied. Moreover, unique patterns of comorbidities, environmental factors, genetic diversity, and paucity of supportive infrastructure may all impact the risk-benefit and outcomes of cancer immunotherapy treatment. Local clinical trials not only directly impact the strengthening of infrastructure but also provide local authorities with better insight into the health economic benefit of cancer immunotherapy, giving impetus to adoption and reimbursement efforts. More local, regional, and multinational collaborative efforts are needed to speed up the evaluation, access, and adoption of ICIs throughout the developing world.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12184393/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Programmed death-1 inhibition increases vaccine-induced T-cell infiltration in patients with prostate cancer.","authors":"Wiem Lassoued, Ravi A Madan, Elisabetta Xue, Daniel Burnett, Kenneth D Canubas, Shania Bailey, Jennifer L Marté, Yo-Ting Tsai, Renee N Donahue, Ismail Baris Turkbey, Antonios Papanicolau-Sengo, Moniquea Williams, Amy Hankin, Manuk Manukyan, Michell Manu, Zhigang Kang, Colin Pritchard, William Dahut, Fatima Karzai, Jeffrey Schlom, Sam Sater, Peter Pinto, James L Gulley","doi":"10.1136/jitc-2024-010851","DOIUrl":"10.1136/jitc-2024-010851","url":null,"abstract":"<p><strong>Background: </strong>Prostate cancer (PC) is the most frequently diagnosed cancer in men worldwide, making up 21% of all cancer cases. Although generally slow-growing, 370,000 men die from PC yearly. Immune checkpoint inhibitors (ICIs) are currently only indicated for the rare cases of microsatellite instability high or tumor mutation burden high disease. Combination therapy strategies that induce immune responses may expand the utility of ICIs. Here, we investigated the safety and efficacy of PROSTVAC, a therapeutic cancer vaccine that targets prostate-specific antigen (PSA), in combination with the programmed cell death protein-1 inhibitor nivolumab (NCT02933255).</p><p><strong>Methods: </strong>We enrolled two cohorts in this trial (phase 1 and 2), both treated with PROSTVAC vaccine and nivolumab. The lead-in cohort had 12 patients with metastatic castration-resistant PC (mCRPC); the neoadjuvant cohort included 12 patients with localized PC who were candidates for radical prostatectomy (RP). We assessed tumor-infiltrating lymphocytes and programmed death-ligand 1 expression in matched formalin-fixed paraffin-embedded samples from baseline biopsies and RP samples. We measured changes in peripheral blood serum analytes, immune cell subsets and antigen-specific T cells targeting PSA, brachyury, and MUC-1 in both cohorts.</p><p><strong>Results: </strong>In the lead-in cohort, two patients had a prolonged complete radiographic response by Response Evaluation Criteria in Solid Tumors V.1.1. In the neoadjuvant cohort, CD4⁺ T helper cell and CD8⁺ T-cell densities were increased by >2-fold in RP samples compared with baseline in most patients (91% and 83% of patients, respectively). Proliferation of CD4⁺ and CD8⁺ T cells also increased in RP samples compared with baseline. Most patients from both cohorts (lead-in and neoadjuvant) had a >2-fold increase in PSA-specific (82% and 58%), MUC-1-specific (64% and 73%), and brachyury-specific (70% and 82%) T cells after therapy. In peripheral blood, we detected increases in proliferative CD4⁺ and CD8⁺ T cells but reductions in total CD4⁺ and CD8⁺ T cells.</p><p><strong>Conclusion: </strong>Neoadjuvant PROSTVAC in combination with nivolumab is associated with increased intratumoral T-cell infiltrates, increased circulating tumor-associated antigen-specific T cells, and with radiographic and biochemical responses in the mCRPC setting. Our findings support the idea that the addition of a vaccine to a tumor-associated antigen might improve the clinical activity of immune checkpoint inhibition.</p><p><strong>Trial registration number: </strong>NCT02933255.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 6","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12184344/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144475343","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}