Journal for Immunotherapy of Cancer最新文献

{"title":"Tumor-specific CD8⁺ T cells from the bone marrow resist exhaustion and exhibit increased persistence in tumor-bearing hosts as compared with tumor-infiltrating lymphocytes.","authors":"Elizabeth M Zawidzka, Luca Biavati, Amy Thomas, Claudio Zanettini, Luigi Marchionni, Robert Leone, Ivan Borrello","doi":"10.1136/jitc-2024-009367","DOIUrl":"10.1136/jitc-2024-009367","url":null,"abstract":"<p><strong>Background: </strong>Immunotherapy is now an integral aspect of cancer therapy. Strategies employing adoptive cell therapy (ACT) have seen the establishment of chimeric antigen receptor (CAR)-T cells using peripheral blood lymphocytes as well as tumor-infiltrating lymphocytes (TILs) with significant clinical results. The bone marrow (BM) is an immunological niche housing T cells with specificity for previously encountered antigens, including tumor-associated antigens from certain solid cancers. This study sought to improve our understanding of tumor-specific BM T cells in the context of solid tumors by comparing them with TILs, and to assess whether there is a rationale for using the BM as a source of T cells for ACT against solid malignancies.</p><p><strong>Methods: </strong>We used the murine B16 melanoma model examining both the endogenous OVA-specific T cell response using an OVA-specific tetramer or examining the OVA-specific response with OVA-specific transgenic CD8+ (OT-1) T cells. Specifically, we compared baseline intrinsic properties of TILs or BM T cells from tumor-bearing mice and their changes following adoptive transfer in the tumor and bone marrow (as well as other compartments when indicated).</p><p><strong>Results: </strong>In tumor-bearing mice, endogenous tumor-specific T cells could be detected in the BM early in the course of tumor progression and possessed a more stem-cell-like and memory phenotype in an unsupervised cluster analysis compared with TILs which appeared more exhausted. The BM and tumor microenvironments significantly impact the fate of T cells. Naïve OT-1 transferred T cells acquired an exhausted phenotype in the tumor but maintained a more memory-like phenotype in the BM with tumor progression. Importantly, in a competitive transfer experiment, BM T cells infiltrated the tumor more efficiently than TILs, displayed a higher polyfunctionality with interleukin-2, interferon-γ, tumor necrosis factor-α production and showed greater persistence compared with TILs.</p><p><strong>Conclusions: </strong>T cells from the BM appear superior to TILs as a source of cells for cellular therapy. They possess a memory-enriched phenotype and exhibit improved effector function, greater persistence within a tumor-bearing host, and the capacity for increased tumor infiltration. These data provide a foundation for further exploring the BM as a source of tumor-specific T cells for ACT in solid malignancies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515642","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":"Phase I study of ribociclib (CDK4/6 inhibitor) with spartalizumab (PD-1 inhibitor) with and without fulvestrant in metastatic hormone receptor-positive breast cancer or advanced ovarian cancer.","authors":"Ana C Garrido-Castro, Noah Graham, Lestat R Ali, Christina Herold, Jennifer Desrosiers, Khanh Do, Heather Parsons, Tianyu Li, Shom Goel, Molly DiLullo, Eileen Wrabel, Amy J Williams, Joyce F Liu, Elizabeth A Mittendorf, Stephanie K Dougan, Nabihah Tayob, Geoffrey I Shapiro, Sara M Tolaney","doi":"10.1136/jitc-2024-010430","DOIUrl":"10.1136/jitc-2024-010430","url":null,"abstract":"<p><strong>Background: </strong>Preclinical evidence suggests that cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors enhance antitumor immunity. We conducted a phase I trial of ribociclib (CDK4/6 inhibitor) plus spartalizumab (PD-1 inhibitor) in patients with hormone receptor (HR)-positive/HER2-negative metastatic breast cancer (MBC) or advanced ovarian cancer (AOC). The combination was also evaluated with fulvestrant in MBC.</p><p><strong>Methods: </strong>In Cohort A, ribociclib was administered on Days 1-21 (28-day cycle) starting at 400 mg, and spartalizumab at 400 mg on Day 1. Dose escalation was followed by expansion in AOC. Fulvestrant was added (Cohort B) with a safety run-in followed by expansion in MBC. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D), and safety and tolerability of the combinations.</p><p><strong>Results: </strong>33 patients enrolled (n=18, Cohort A; n=15, Cohort B). The RP2D of ribociclib in both cohorts was 600 mg. Treatment-related adverse events in >20% of patients in either cohort were neutropenia, fatigue, anemia, thrombocytopenia, hypertransaminasemia, maculopapular rash, fatigue, and nausea. Hypertransaminasemia occurred in 66.7% (AST) and 46.7% (ALT) of patients in Cohort B, including 46.7% and 40.0%, respectively, of grade 3 or 4 events. Two confirmed partial responses were observed (13.3%) in Cohort B, in patients with low baseline serum thymidine kinase activity, coupled with an increase on-treatment. Peripheral blood flow cytometry across patients demonstrated on-target drug binding with increases in PD-1 occupancy and activated CD8⁺ T cells during treatment, irrespective of response. PD-L1-positivity, tumor-infiltrating lymphocytes, or tumor mutational burden did not correlate with progression-free survival (PFS). Several copy-number variations detected with next-generation sequencing correlated with PFS.</p><p><strong>Conclusions: </strong>Ribociclib with spartalizumab and fulvestrant showed limited efficacy and elevated hepatotoxicity, precluding further development. Correlative analyses revealed treatment-induced immunological effects, and genomic alterations associated with PFS.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515619","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":"Association of 5α-reductase inhibitor prescription with immunotherapy efficacy in metastatic renal cell carcinoma: a multicenter retrospective analysis.","authors":"Bisheng Cheng, Jilin Wu, Ke Chen, Weijia Li, Jianghua Yang, WenTai Shangguan, Lin Yang, Wenxue Huang, Cunzhen Ma, Zhuohang Li, Boyuan Sun, Qiong Wang, Hai Huang, Peng Wu","doi":"10.1136/jitc-2024-011154","DOIUrl":"10.1136/jitc-2024-011154","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic renal cell carcinoma (mRCC), but response rates remain heterogeneous, and reliable predictive biomarkers are lacking. Recent studies suggest that androgen receptor (AR) signaling plays a role in regulating CD8⁺ T-cell function, implying that 5α-reductase inhibitors (5-ARIs), which lower androgen activity, could enhance antitumor immunity and improve clinical outcomes in patients receiving immunotherapy. This study retrospectively investigates the impact of a history of 5-ARI use (≥12 months) on the efficacy of ICIs in mRCC.</p><p><strong>Methods: </strong>We conducted a multicenter retrospective cohort study of 185 patients with mRCC who received ICIs. Patients were stratified based on their history of 5-ARI use. Baseline characteristics included age, body mass index, International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk group, programmed death-ligand 1 (PD-L1) expression levels, tumor stage, and metastasis sites. The primary endpoints were progression-free survival (PFS) and overall survival (OS), analyzed using Cox proportional hazards models. Secondary endpoints included objective response rate (ORR) and disease control rate (DCR). Key immunological insights were gained through single-cell RNA sequencing analysis of tumor samples.</p><p><strong>Results: </strong>Patients with a history of 5-ARI use demonstrated improved ORR (59.8% vs 39.8%, p=0.0075) and DCR (87.0% vs 78.7%, p=0.1747) compared with those without. The median PFS and OS were significantly longer in the 5-ARI group, with HRs of 0.64 (95% CI: 0.47 to 0.86, p=0.0085) for PFS and 0.65 (95% CI: 0.47 to 0.90, p=0.0271) for OS. Subgroup analysis further indicated enhanced ICI efficacy with 5-ARI use across age, IMDC risk scores, and PD-L1 expression levels. Single-cell RNA sequencing analysis revealed that 5-ARI treated patients exhibited a reduced presence of regulatory T cells and CD8 T-cell exhaustion (CD8 Tex), and lower programmed cell death protein-1 expression in CD8 Tex cells, suggesting an immunologically favorable modification of the tumor.</p><p><strong>Conclusion: </strong>A history of 5-ARI use is associated with improved responses to ICI therapy in mRCC, potentially through AR-related modulation of CD8⁺ T-cell activity and favorable alterations in the immune microenvironment. These findings support further investigation into androgen-targeted approaches as adjunctive strategies in immunotherapy for RCC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865730/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515799","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":"Disruption of GPSM1/CSF1 signaling reprograms tumor-associated macrophages to overcome anti-PD-1 resistance in colorectal cancer.","authors":"Yang Chen, Huiqing Jia, Xiangyan Zhang, Han Zhao, Yujing Xiao, Na Li, Yifan Yao, Xiaoming Xing","doi":"10.1136/jitc-2024-010826","DOIUrl":"https://doi.org/10.1136/jitc-2024-010826","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint blockade (ICB) therapies, particularly anti-PD-1, benefit only a limited subset of colorectal cancer (CRC) patients. G-protein signaling modulator 1 (GPSM1) is implicated in immunity and oncology, yet its role in regulating the CRC tumor microenvironment (TME) and contributing to anti-PD-1 resistance remains poorly understood.</p><p><strong>Methods: </strong>We employed single-cell RNA sequencing and multiplex immunofluorescence on tumor samples from anti-PD-1-resistant CRC patients to evaluate GPSM1 expression and its impact on macrophage polarization. An orthotopic CRC xenograft model in C57BL/6 mice was used to assess the role of GPSM1 in vivo. An in vitro co-culture system, alongside mass cytometry and flow cytometry, explored GPSM1's biological functions within the TME. We further used ChIP-PCR, mass spectrometry, and co-immunoprecipitation to elucidate the mechanisms regulating GPSM1 activity.</p><p><strong>Results: </strong>GPSM1 expression was significantly elevated in anti-PD-1-resistant CRC tissues. Enhanced GPSM1 levels promoted anti-PD-1 resistance by driving macrophage polarization toward an immunosuppressive M2 phenotype, facilitating their infiltration into the TME. We identified the deubiquitinase USP9X as a key factor preventing GPSM1 degradation through K63-polyubiquitination. This stabilization of GPSM1 led to MEIS3 nuclear translocation, activating macrophage colony-stimulating factor expression. Importantly, ruxolitinib emerged as a promising GPSM1-targeting candidate, demonstrating improved efficacy in combination with anti-PD-1 therapy in both microsatellite instability-high and microsatellite stable CRC models.</p><p><strong>Conclusions: </strong>Our findings highlight the pivotal role of GPSM1-driven M2 macrophage infiltration in mediating anti-PD-1 resistance in CRC. Targeting GPSM1 offers a novel therapeutic strategy to enhance ICB efficacy, potentially broadening the patient population that may benefit from these therapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Novel post-translational modification learning signature reveals B4GALT2 as an immune exclusion regulator in lung adenocarcinoma.","authors":"Pengpeng Zhang, Dingli Wang, Guangyao Zhou, Shuai Jiang, Ge Zhang, Lianmin Zhang, Zhenfa Zhang","doi":"10.1136/jitc-2024-010787","DOIUrl":"10.1136/jitc-2024-010787","url":null,"abstract":"<p><strong>Background: </strong>Lung adenocarcinoma (LUAD) presents significant challenges in prognosis and treatment efficacy evaluation. While post-translational modifications are known to influence tumor progression, their prognostic value in LUAD remains largely unexplored.</p><p><strong>Methods: </strong>We developed a post-translational modification learning signature (PTMLS) using machine learning techniques, analyzing data from 1231 LUAD patients across seven global cohorts. The signature's efficacy in predicting immunotherapy response was evaluated using 12 immunotherapy cohorts spanning multiple cancer types (n=1201). An in-house LUAD tissue cohort (n=171) was used to validate beta-1,4-galactosyltransferase 2's (B4GALT2's) prognostic significance. The role of B4GALT2 in immune exclusion was investigated through in vivo and in vitro experiments.</p><p><strong>Results: </strong>The established PTMLS exhibited exceptional predictive capabilities in LUAD patient outcomes, surpassing the efficacy of 98 existing LUAD prognostic indicators. The system's predictive value was validated across diverse malignancy categories for immunotherapeutic response assessment. From a biological perspective, significant correlations were observed between PTMLS and immunological parameters, whereby elevated PTMLS levels were characterized by attenuated immune responses and immunologically cold neoplastic features. Within the PTMLS framework, B4GALT2 was identified as a crucial molecular component (r=0.82, p<0.05), and its heightened expression was linked to unfavorable clinical outcomes in LUAD cases, particularly in specimens exhibiting CD8-depleted phenotypes. The spatial distribution patterns between B4GALT2 and immune cell populations, specifically CD8+ T lymphocytes and CD20+ B lymphocytes, were elucidated through multiplexed immunofluorescence analysis. Laboratory investigations subsequently established B4GALT2's regulatory influence on LUAD cellular expansion in both laboratory cultures and animal models. Significantly, suppression of B4GALT2 was found to enhance CD8+ T lymphocyte populations and their functional status, thereby potentiating anti-programmed cell death protein 1 immunotherapeutic efficacy in animal studies. This phenomenon was characterized by reduced CD62L+CD8 T lymphocyte levels alongside elevated GZMB+/CD44+/CD69+CD8 T cell populations.</p><p><strong>Conclusion: </strong>The developed PTMLS system represents an effective instrument for individualized prognostic evaluation and immunotherapy stratification in both LUAD and diverse cancer populations. The identification of B4GALT2 as a previously unrecognized oncogenic factor involved in immune exclusion presents a novel therapeutic avenue for LUAD treatment and immunotherapy optimization.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515487","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":"Targeted delivery of CCL3 reprograms macrophage antigen presentation and enhances the efficacy of immune checkpoint blockade therapy in hepatocellular carcinoma.","authors":"Muqi Liu, Linzhe Li, Lu Cao, Wei Li, Xingshi Gu, Min Yang, Di Wu, Yanan Li, Yao Deng, Juan Zhang, Cejun Yang, Qi Liang, Huaping Liu, Pengfei Rong, Xiaoqian Ma, Wei Wang","doi":"10.1136/jitc-2024-010947","DOIUrl":"10.1136/jitc-2024-010947","url":null,"abstract":"<p><strong>Background: </strong>Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related deaths worldwide, especially in advanced stages where limited treatment options result in poor prognosis. The immunosuppressive tumor immune microenvironment (TIME), characterized by low immune cell infiltration and exhaustion, limits immunotherapy efficacy. To address this, our study investigates the role of C-C motif chemokine ligand 3 (CCL3) in modulating the HCC TIME.</p><p><strong>Methods: </strong>We analyzed CCL3 expression in human HCC samples from The Cancer Genome Atlas database, focusing on its correlation with inflammatory gene signatures and immune cell infiltration. High-dimensional single-cell RNA sequencing (scRNA-seq), flow cytometry, and multiplex immunofluorescence were used to investigate CCL3's effects on macrophage function and T cell activation. The biological impact of CCL3 on macrophages was assessed using co-culture systems, confocal imaging, metabolite detection, and inhibition assays. Preclinical HCC models and ex vivo tumor fragment assays further explored how CCL3 modulates immune responses and enhances immune checkpoint blockade efficacy.</p><p><strong>Results: </strong>Our study shows that CCL3 is suppressed in the tumor microenvironment and positively correlates with immune infiltration and inflammatory responses. Targeted liver delivery of rAAV-Ccl3 reprograms the immune microenvironment in HCC, promoting immune cell recruitment and tertiary lymphoid structure formation, thus suppressing tumor growth via immune engagement. Through scRNA-seq, flow cytometry, and multiplex immunofluorescence, we found that CCL3 enhances macrophage antigen uptake and activates cytotoxic T cells. In vivo and in vitro experiments confirmed that CCL3 facilitates T cell infiltration and upregulates MHC II expression on macrophages, enhancing antigen presentation. The CCL3-CCR5 pathway also boosts macrophage metabolism, increasing lysosomal activity and antigen uptake, thereby strengthening adaptive immune responses and increasing sensitivity to immune checkpoint blockade therapies in preclinical models.</p><p><strong>Conclusions: </strong>This study highlights the pivotal role of CCL3 in reshaping the TIME and enhancing antitumor immunity in HCC. By promoting immune cell recruitment and enhancing antigen presentation, CCL3 demonstrates significant potential to improve the efficacy of immunotherapy, particularly in combination with immune checkpoint inhibitors. Targeting CCL3 may help to overcome the immunosuppressive TIME in HCC and improve patient outcomes.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11848677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482918","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":"Phosphatidylserine as a tumor target for CAR-T cell therapy.","authors":"Celia Martín-Otal, Inés Sánchez-Moreno, Alvaro Gómez-Morón, Carla Castro, Noelia Casares, Flor Navarro, Marta Gorraiz, Pedro Justicia-Lirio, Felix Pareja, María Collantes, Iván Peñuelas, Mercedes Iñarrairaegui, Bruno Sangro, Isabel Vivas, Marta Larrayoz, Juan Roberto Rodriguez, Felipe Prosper, Sandra Hervas-Stubbs, Noa Martin-Cofreces, Juan Jose Lasarte, Teresa Lozano","doi":"10.1136/jitc-2024-009468","DOIUrl":"10.1136/jitc-2024-009468","url":null,"abstract":"<p><strong>Background: </strong>Phosphatidylserine (PS) exposed on apoptotic cells promotes immune clearance of dead cells without inducing inflammation. Conversely, PS exposure on live tumor cells promotes an immunosuppressive tumor microenvironment that hinders antitumor immune responses. After confirming elevated PS levels in various tumor cell lines and cancer tissues, we aimed to investigate its potential as a target antigen for chimeric antigen receptor T cell (CAR-T) therapy.</p><p><strong>Methods: </strong>We used two different approaches to target PS. First, we employed the adaptor proteins, EDAnnexin or BCMAnnexin comprising annexin V and EDA (extra domain A of fibronectin) or B-cell maturation antigen (BCMA) antigens, to redirect the lytic activity of EDA CAR-T or BCMA CAR-T cells toward PS-expressing tumor cells. In a second approach, we developed an annexin V-based CAR (Anxa CAR-T) to directly recognize PS-positive tumor cells.</p><p><strong>Results: </strong>The adaptors proteins EDAnnexin and BCMAnnexin successfully redirected EDA CAR-T or BCMA CAR-T cell activity, leading to an efficient recognition of PS⁺ tumor cells in vitro. However, the established immunological synapse differs significantly from that observed when CAR-T cells recognize the tumor cells directly. In vivo administration of the adaptor proteins, combined with the corresponding CAR-T cells, displayed antitumor activity in mice bearing PS⁺ tumors. Regarding the second approach, Anxa CAR-T cells effectively recognized and killed PS⁺ tumor cells in vitro. Nonetheless, PS exposure on T-cell membranes during T-cell activation impeded efficient Anxa CAR-T cell manufacturing due to fratricide. By optimizing retroviral dose to reduce Anxa CAR expression on the cell membrane, or by using the multikinase inhibitor dasatinib, the fratricide effect was mitigated, enabling successful Anxa CAR^Low-T cell production. Remarkably, Anxa CAR^Low-T cells demonstrated antitumor activity in in vivo murine models of PS⁺ hepatocarcinoma and teratocarcinoma. No signs of toxicity were observed after Anxa CAR-T cell administration.</p><p><strong>Conclusions: </strong>PS holds promise as a target antigen for CAR-T cell therapy, underscoring the need to address fratricide as a key challenge in the development of PS-targeting CAR-T cells.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11848672/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143482692","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":"Ethanol inhibits the growth and metastasis of hepatocellular carcinoma by inducing immunogenic cell death.","authors":"Yu-Chen Hsu, Meng-Chuan Wu, Meng Tzu Weng, Ying-Te Lee, Huei-Chi Chou, Hsuan-Shu Lee, Li-Fang Wang, Jin-Chuan Sheu, Chien-Hung Chen","doi":"10.1136/jitc-2024-010472","DOIUrl":"10.1136/jitc-2024-010472","url":null,"abstract":"<p><strong>Background: </strong>Immunogenic cell death (ICD) can elicit an adaptive immune response with significant antitumor effects. Percutaneous ethanol injection therapy has been applied as tumor ablation for small hepatocellular carcinoma (HCC). However, it was not clear whether ethanol can elicit ICD. The aim of this study is to investigate the role of ethanol as an ICD inducer.</p><p><strong>Methods: </strong>HCC cell lines were treated with low-concentration ethanol and ICD markers, such as calreticulin, high-mobility group box 1, and ATP were assayed. The mouse vaccination-rechallenge assay was used to further confirm ethanol as an ICD inducer. Western blot and real-time PCR were used to investigate ICD-related endoplasmic reticulum (ER) stress and signaling pathways. The genes with differential expression levels between primary and distant tumors were analyzed by nCounter gene expression. Intratumoral injection of ethanol was done to investigate the abscopal effect.</p><p><strong>Results: </strong>The low-concentration ethanol could induce ICD in HCC cell lines through unfolded protein responses initiated by ER stress and multiple cell-death pathways. Intratumoral injections of low-concentration ethanol had significantly direct and abscopal antitumor effects in mouse models of both subcutaneous and orthotopic HCC. nCounter gene expression analysis in primary and distant tumors revealed the activation of various immune-response pathways, notably those mediated by CD8 T cells and the interferon pathway. Vaccinating mice with low-concentration ethanol-treated HCC cells successfully inhibited metastasis in both intravenous and intrasplenic metastasis models.</p><p><strong>Conclusions: </strong>Our results suggest that low-concentration ethanol could serve as an inducer of ICD. Low-concentration ethanol could potentially improve therapeutic antitumor immunity by inducing substantial ICD.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843001/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468048","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":"Skin mutation burden drives adaptive immunity and response to immunotherapy.","authors":"Timothy Looney","doi":"10.1136/jitc-2024-011062","DOIUrl":"10.1136/jitc-2024-011062","url":null,"abstract":"<p><p>Numerous studies over the past century have reported an inverse correlation between lifetime solar ultraviolet radiation (UV) exposure and all-cancer incidence and mortality. For decades, this relationship was hypothesized to reflect the action of photosynthesized vitamin D, though subsequent clinical trials have failed to demonstrate the expected anti-cancer properties. Rather than a consequence of vitamin D, I hypothesize that this inverse correlation reflects the immune stimulatory action of UV-derived skin neoantigens. Over time, such UV-mediated immune education drives immune repertoire diversification and superior adaptive immune responses to infectious disease and cancer. This hypothesis would explain the strong positive selection for light skin pigmentation following the out-of-Africa migration among humans inhabiting northerly latitude regions, and the longstanding racial disparities in cancer and infectious disease observed in North America. It suggests that the skin comprises an important reservoir of anti-cancer T cells that may be harnessed for anti-cancer therapy, and that skin mutation burden (SMB) may serve as a predictive biomarker of immunotherapy response. I propose a novel, non-invasive method for quantifying SMB as a biomarker.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843019/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468109","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":"Mimicry-based strategy between human and commensal antigens for the development of a new family of immune therapies for cancer.","authors":"Alice Talpin, Ana Maia, Jean-Marie Carpier, Guillaume Kulakowski, Lucie Aubergeon, Jerome Kervevan, Camille Gaal, Francesco Strozzi, Coline Billerey, Ludivine Amable, Tifanny Mersceman, Alexandrine Garnier, Càtia Oliveira, Carolina Calderon, Diana Bachrouche, Chloé Ventujol, Léa Bernard, Amandine Manteau, Jennifer Martinez, Michaël Bonnet, Julie Noguerol, Karl Laviolette, Laura Boullerot, Marine Malfroy, Gregoire Chevalier, Olivier Adotevi, Olivier Joffre, Ahmed Idbaih, Maria Vieito, Francois Ghiringhelli, Agostina Stradella, Ghazaleh Tabatabai, Michael C Burger, Iris Mildenberger, Ulrich Herrlinger, David A Reardon, Wolfgang Wick, Cecile Gouttefangeas, Christophe Bonny, Laurent Chene, Joao Gamelas Magalhaes","doi":"10.1136/jitc-2024-010192","DOIUrl":"10.1136/jitc-2024-010192","url":null,"abstract":"<p><strong>Background: </strong>Molecular mimicry between commensal bacterial antigens and tumor-associated antigens (TAAs) has shown potential in enhancing antitumor immune responses. This study leveraged this concept using commensal bacterial antigens, termed OncoMimics, to induce TAA-derived peptide (TAAp)-specific cross-reactive cytotoxic T cells and improve the efficacy of peptide-based immunotherapies.</p><p><strong>Methods: </strong>The discovery of OncoMimics primarily relied on a bioinformatics approach to identify commensal bacteria-derived peptide sequences mimicking TAAps. Several OncoMimics peptide (OMP) candidates were selected in silico based on multiple key parameters to assess their potential to elicit and ameliorate immune responses against TAAs. Selected OMPs were synthesized and tested for their affinity and stability on the major histocompatibility complex (MHC) in vitro and for their capacity to elicit cross-reactive OMP-specific/TAAp-specific CD8+T cell responses in human leukocyte antigen (HLA)-A2-humanized mice, human peripheral blood mononuclear cells (PBMC) and patients with cancer.</p><p><strong>Results: </strong>Selected OMPs demonstrated superior HLA-A2 binding affinities and stabilities compared with homologous TAAps. Vaccination of HLA-A2-humanized mice with OMPs led to the expansion of OMP-specific CD8+T cells that recognize both OMPs and homologous TAAps, exhibiting cytotoxic capacities towards tumor antigens and resulting in tumor protection in a prophylactic setting. Using PBMCs from HLA-A2+healthy donors, we confirmed the ability of OMPs to elicit potent cross-reactive OMP-specific/TAAp-specific CD8⁺ T-cell responses. Interestingly, we observed a high prevalence of OMP-specific T cells across donors. Cytotoxicity assays revealed that OMP-stimulated human T cells specifically targeted and killed tumor cells loaded with OMPs or TAAps. Preliminary data from an ongoing clinical trial (NCT04116658) support these findings, indicating that OMPs elicit robust OMP-specific/TAAp-specific CD8+T cell responses in patients. Initial immunomonitoring data revealed sustained T-cell responses over time, with T cells maintaining a polyfunctional, cytotoxic and memory phenotype, which is critical for effective antitumor activity and long-term immune surveillance.</p><p><strong>Conclusions: </strong>These findings suggest that leveraging naturally occurring commensal-derived antigens through OMPs could significantly remodel the tumor immune landscape, offering guidance for a promising strategy for cancer peptide-based immunotherapies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11842988/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143468039","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}