Journal for Immunotherapy of Cancer最新文献

{"title":"GP73: the key to unlocking immunotherapies efficacy in solid tumors?","authors":"Rebecca J Bayliss, Alan L Parker","doi":"10.1136/jitc-2025-011989","DOIUrl":"10.1136/jitc-2025-011989","url":null,"abstract":"<p><p>Resident Golgi protein 73 (GP73) is expressed in many healthy tissues, however overexpression is associated with both viral infections and cancer. As an oncoprotein, GP73 drives tumor progression and plays a fundamental role in immune regulation. A recent publication illustrates a role for GP73 in T-cell antitumor immunity employing GP73 genetically depleted T-cell mouse models. GP73-deficient T-cells were found to detrimentally affect CD8+T cell cytotoxicity and glycolysis primarily due to its interaction with Hypoxia-inducible factor 1α and mTOR levels in hypoxic cells, suggesting a key role for GP73 in T-cell cytotoxicity within the hypoxic tumor microenvironment. This finding opens the door to the potential development of GP73 targeting through ectopic expression of GP73 which was found to restore glycolysis and therefore T-cell cytotoxicity resulting in tumor regression. In addition, GP73 was found to be a potential biomarker to inform clinical treatment of patients undergoing immunotherapy. Could GP73 be the key to establishing a therapeutic strategy for generating improved patient responses to immunotherapy?</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083270/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143981919","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":"Regional distribution of HLA frequencies in the USA: implications for TCR-based therapies.","authors":"Christian Roy, Tomasz Sewastianik, Ileana Saenz, Gregory J Opiteck, Sean Stagg, Martin Maiers, Dirk Nagorsen","doi":"10.1136/jitc-2024-011441","DOIUrl":"10.1136/jitc-2024-011441","url":null,"abstract":"<p><p>Understanding regional distribution of HLA frequencies is crucial for optimizing enrollment in HLA-restricted clinical trials and to promote trial diversity per the Food and Drug Administration's 2020 mandate. Using US HLA frequency data and census demographics we developed a method to create high-resolution HLA class 1 genotypic frequency maps. Analyzing HLA-A*11:01 and HLA-B*58:01 as alleles of interest, we found significant US regional variations. HLA-A*11:01, which presents KRAS neoantigen mutations targeted by TCR T-cell therapies, showed 10-15% genotypic frequency (national average 11.2%), with western US states 1.5 times higher than average and local variations within California (10-19%). These insights can be used to guide clinical trial site selection, for example, in National Cancer Institute (NCI) cancer center catchment areas. For HLA-B*58:01, which reacts pharmacogenetically with allopurinol and results in severe cutaneous adverse reactions, Mississippi had a high frequency among US states, which could be used to guide potential public safety campaigns. This method can identify regions with high HLA type representation, aiding efficient patient identification and enrollment for HLA-specific clinical trials and health-awareness efforts.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163332/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015012","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":"Asia's emergence in cancer immunotherapy: challenges and opportunities.","authors":"Yan Li, Joe Yeong, Bernard A Fox, Cheng Sun","doi":"10.1136/jitc-2024-011278","DOIUrl":"10.1136/jitc-2024-011278","url":null,"abstract":"<p><p>Asia's role in cancer immunotherapy research is rapidly expanding, driven by cutting-edge facilities, innovative technologies, and collaborative efforts. This commentary examines the region's growing impact, highlighting key clinical trials, emerging research hubs, and unique challenges that we face. It discusses the need for standardization in cell and gene therapies, and more broadly all immunotherapies, addressing cost and accessibility issues. We examine the implications of genetic diversity in Asian populations as well as cultural and linguistic factors that affect clinical trials and patient care. The analysis extends to emerging opportunities in technological innovation and international collaboration, while addressing critical challenges in regulatory oversight, data transparency, and intellectual property protection. The success of the recent SITC-World Immunotherapy Council-Asia conference is showcased as a catalyst for future collaborations. By tackling these challenges and using innovations, Asian countries can significantly contribute to global advancements in cancer immunotherapy, potentially improving outcomes for patients worldwide.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083353/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144024957","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":"Combination of a therapeutic cancer vaccine targeting the endogenous retroviral envelope protein ERVMER34-1 with immune-oncology agents facilitates expansion of neoepitope-specific T cells and promotes tumor control.","authors":"Maria Del Mar Maldonado, Maria Gracia-Hernandez, Loc Huu Le, Masafumi Iida, James L Gulley, Renee N Donahue, Claudia Palena, Jeffrey Schlom, Duane H Hamilton","doi":"10.1136/jitc-2024-011378","DOIUrl":"10.1136/jitc-2024-011378","url":null,"abstract":"<p><strong>Background: </strong>Endogenous retroviruses (ERVs) are remnants of retrovirus germline infections that occurred over the course of evolution and constitute between 5% and 8% of the human genome. While ERVs tend to be epigenetically silenced in normal adult human tissues, they are often overexpressed in carcinomas and may represent novel immunotherapeutic targets. This study characterizes the ERV envelope protein ERVMER34-1 as a target for a therapeutic cancer vaccine.</p><p><strong>Methods: </strong>The expression of ERVMER34-1 in multiple healthy adult and cancer tissues was assessed, as was its immunogenicity, to ascertain whether specific T cells could lyse human carcinoma cell lines expressing ERVMER34-1. Furthermore, the ability of a rationally designed ERVMER34-1-targeted therapeutic vaccine to induce tumor clearance in two murine carcinoma models expressing ERVMER34-1 was examined either as a monotherapy or in combination with anti-programmed cell death protein-1/programmed death-ligand 1 monoclonal antibody (mAb) or the interleukin-15 superagonist N-803.</p><p><strong>Results: </strong>The ERVMER34-1 protein was shown to be overexpressed in 232/376 of human carcinomas analyzed while being absent in most healthy adult tissues. High levels of ERVMER34-1 RNA expression associate with decreased survival in uveal melanoma, adenoid cystic, and head and neck carcinomas. ERVMER34-1-specific T cells were detected in peripheral blood mononuclear cells (PBMCs) of patients with cancer but not healthy donors following an overnight stimulation. However, reactive T cells are readily expanded from both healthy donor and patient with cancer PBMCs following a 7- day in vitro stimulation. Furthermore, ERVMER34-1-specific T cells selectively kill human carcinoma cell lines expressing ERVMER34-1. A novel, rationally designed, therapeutic cancer vaccine targeting ERVMER34-1 mediated tumor control in established syngeneic murine tumors expressing the full-length ERVMER34-1 protein. When combined with checkpoint blockade, the vaccine promoted expansion of neoepitope-reactive T cells whose function was further enhanced when combined with N-803. This expansion of neoepitope-reactive T cells was associated with tumor control.</p><p><strong>Conclusions: </strong>This study reveals the potential of a vaccine that targets the retroviral envelope protein ERVMER34-1 and supports its continued development toward clinical testing as a new class of therapeutic cancer vaccine.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12163335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144007754","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":"Associations between immune checkpoint inhibitor response, immune-related adverse events, and steroid use in RADIOHEAD: a prospective pan-tumor cohort study.","authors":"Zoe Quandt, Anastasia Lucas, Samantha I Liang, EnJun Yang, Samantha Stone, Muhammad Zaki Hidayatullah Fadlullah, Nicholas L Bayless, Sara Siebel Marr, Marshall A Thompson, Lacey J Padron, Samantha Bucktrout, Lisa H Butterfield, Aik Choon Tan, Kevan C Herold, Jeffrey A Bluestone, Mark S Anderson, Christine N Spencer, Arabella Young, John E Connolly","doi":"10.1136/jitc-2025-011545","DOIUrl":"10.1136/jitc-2025-011545","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) have led to enduring responses in subsets of patients with cancer. However, these responses carry the risk of immune-related adverse events (irAEs), which can diminish the overall benefit of ICI treatment. While associations between irAE development and overall survival have been increasingly documented, there is a need for further understanding of these connections in large prospective real-world cohorts.</p><p><strong>Methods: </strong>The Resistance Drivers for Immuno-Oncology Patients Interrogated by Harmonized Molecular Datasets (RADIOHEAD) study, a pan-tumor, prospective cohort of 1,070 individuals undergoing standard of care first-line ICI treatment, aims to identify factors driving irAEs and clinical response. Clinical data and longitudinal blood samples were collected prospectively at multiple time points from 49 community-based oncology clinics across the USA. Structured, harmonized clinical data underwent unbiased statistical analysis to uncover predictors of real-world overall survival (rwOS) and risk factors for irAEs.</p><p><strong>Results: </strong>Across 1,070 participants' treatment courses, RADIOHEAD accumulated over 4,500 clinical data points. Patients experiencing any irAE (25.4%, n=272) exhibited significantly improved rwOS in the pan-tumor cohort (n=1,028, HR=0.41, 95% CI=(0.31, 0.55)). This association persisted when adjusting for age and metastatic disease in multivariate time-dependent Cox proportional hazard analysis, and was consistent across major tumor subtypes, including lung cancer and melanoma. Skin and endocrine irAEs of any grade were strongly associated with improved rwOS (Cox proportional hazard analysis, skin, p=2.03e-05; endocrine, p=0.0006). In this real-world cohort, the irAE rate appeared lower than those reported in clinical trials. Patients receiving corticosteroids prior to initiation of ICI treatment had significantly worse survival outcomes than non-users (HR 1.37, p=0.0054), with a stronger association with systemic steroid use (HR 1.75, p=0.0022). The risk of irAE was increased by exposure to combination immunotherapy relative to monotherapy (OR 4.17, p=2.8e-7), zoster vaccine (OR 2.4, p=5.2e-05), and decreased by prior chemotherapy (OR 1.69, p=0.0005).</p><p><strong>Conclusion: </strong>The RADIOHEAD cohort is a well-powered, real-world cohort that clearly demonstrates the association between irAE development with improved response and baseline steroid use with worse response to ICI treatment after adjustment for survival bias.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083316/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014042","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":"Long-term mortality outcomes among immunotherapy recipients treated with dupilumab for the management of cutaneous immune-related adverse events.","authors":"Sara Khattab, Guihong Wan, Suzanne Xu, Cameron Moseley, Matthew Tran, Emma Beagles, Chuck Lin, Bonnie W Leung, Marjan Azin, Ninghui Hao, Kerry L Reynolds, Shadmehr Demehri, Nicole R LeBoeuf, Yevgeniy R Semenov","doi":"10.1136/jitc-2024-010638","DOIUrl":"10.1136/jitc-2024-010638","url":null,"abstract":"<p><strong>Background: </strong>Dupilumab has been added to National Cancer Comprehensive Network guidelines as a therapeutic strategy for managing certain cutaneous immune-related adverse events (cirAEs) from immune checkpoint blockade (ICB). However, little is known about the implications of dupilumab for cancer outcomes in this population. In this multi-institutional study, we evaluate the impact of dupilumab treatment on survival among ICB recipients.</p><p><strong>Methods: </strong>We conducted a multi-institutional retrospective cohort study of ICB recipients from the Mass General Brigham Healthcare System and Dana-Farber Cancer Institute. The dupilumab group was compared with two control groups who did not receive dupilumab: with and without cirAEs (control groups 1 and 2, respectively) that were 1:2 matched on sex, race, age at ICB initiation, Charlson Comorbidity Score, year of ICB initiation, and ICB type. Manual chart review was performed to obtain cirAE characteristics, systemic glucocorticoid use, dupilumab treatment, vital status, and last contact date. Time-varying multivariable Cox proportional hazards regressions were used to evaluate the impact of dupilumab on overall survival, adjusted for sex, race, age at ICB initiation, ICB type, Charlson Comorbidity Index score, cancer type, cancer stage at ICB initiation, and systemic glucocorticoid use.</p><p><strong>Results: </strong>A total of 53 cirAE patients treated with dupilumab were compared with two control groups of 106 patients each. Most patients receiving dupilumab demonstrated either complete or partial resolution of their cirAE (88.7%). In multivariable modeling, the overall survival of the dupilumab group was not significantly different from control group 1 (HR=0.74, 95% CI: 0.35 to 1.60, p=0.5) or control group 2 (HR=0.70, 95% CI: 0.32 to 1.51, p=0.4). However, the use of systemic glucocorticoids within 2 years after ICB initiation was associated with poorer overall survival when comparing the dupilumab group to control group 1 (HR=2.03, 95% CI: 1.04 to 3.96, p=0.039) and control group 2 (HR=2.21, 95% CI: 1.25 to 3.91, p=0.006).</p><p><strong>Conclusions: </strong>This study suggests that dupilumab is an effective therapy for recalcitrant cirAEs and does not adversely impact mortality. Due to the observed detrimental effects of systemic glucocorticoid therapy, this study suggests the need to shift away from systemic glucocorticoid immunosuppression and toward targeted immune modulators for irAE management, though prospective randomized trials are necessary to investigate this.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12083386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143984545","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":"Combinatorial treatment with upadacitinib abrogates systemic toxicity of a tumor-targeted IL-2 fusion protein.","authors":"Giulia Rotta, Eleonora Prodi, Frauke Seehusen, Matilde Bocci, Francesco Prisco, Ettore Gilardoni, Claudia Comacchio, Cornelia Halin, Emanuele Puca, Dario Neri, Sheila Dakhel Plaza","doi":"10.1136/jitc-2024-010831","DOIUrl":"https://doi.org/10.1136/jitc-2024-010831","url":null,"abstract":"<p><strong>Background: </strong>The administration of recombinant interleukin 2 (IL-2) in oncology is frequently hampered by dose-limiting toxicities, including potentially lethal vascular leak syndrome. Antibody-IL-2 fusion proteins capable of preferential tumor localization have shown encouraging signs of activity in clinical trials; however, they typically cause side effects shortly after intravenous administration, which may limit escalation to curative doses. There is an urgent need to engineer IL-2 products with \"activity-on-demand\" able to mask on-target off-tumor IL-2 activity without compromising therapeutic efficacy.</p><p><strong>Methods: </strong>To design IL-2 biopharmaceuticals with \"activity-on-demand\", which would be non-toxic on administration but regain activity at the tumor site, we explored the therapeutic potential of the co-administration of signaling inhibitors with matched pharmacokinetic properties. In this work, we used the tumor-homing F8-IL2 fusion protein, specific to a splice variant of fibronectin, and masked off-tumor toxicity by co-administration of upadacitinib, which rapidly clears from circulation. Vascular leak syndrome was monitored by histopathological analysis, the extent of peripheral edema, and cytokine levels. Immune profiling of the tumors and secondary lymphoid organs was performed by flow cytometry.</p><p><strong>Results: </strong>In immunocompetent tumor-bearing mice, the combinatorial treatment significantly improved tolerability without any detectable loss of therapeutic activity, protecting the mice from body weight loss, uncontrolled systemic cytokine release, and severe vascular leak syndrome manifestations, including peripheral edema. F8-IL2 efficiently controlled tumor growth and retained its immunological activity within the neoplastic mass, as evidenced by the massive natural killer and cytotoxic T-cell infiltrates.</p><p><strong>Conclusions: </strong>This study suggests that combinatorial treatments enable the administration of potentially curative doses of targeted IL-2 products while sparing healthy organs from life-threatening toxicities.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067867/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144003108","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":"Novel oncolytic vaccinia virus armed with interleukin-27 is a potential therapeutic agent for the treatment of murine pancreatic cancer.","authors":"Yangyang Jia, Yanru Wang, Guanghao Zhao, Yong Yang, Wenyi Yan, Ruimin Wang, Bing Han, Lihong Wang, Zhe Zhang, Lijuan Chen, Nicholas R Lemoine, Louisa S Chard Dunmall, Pengju Wang, Yaohe Wang","doi":"10.1136/jitc-2024-010341","DOIUrl":"10.1136/jitc-2024-010341","url":null,"abstract":"<p><strong>Background: </strong>Pancreatic cancer has a complex immunosuppressive tumor microenvironment (TME), which is highly resistant to conventional therapies and emerging cancer immunotherapies. Oncolytic viruses are multifaceted killers of malignant tumors, which can selectively infect, replicate in and lyse tumor cells, release tumor-associated antigens to stimulate specific antitumor immune responses, and recruit immune cells into the TME, turning \"cold\" tumors \"hot\". Here, we report a novel <i>vaccinia virus</i> (VV), VVLΔTKΔN1LΔA41L (with deletion of thymidine kinase (TK), N1L, and A41L genes) armed with interleukin 27 (IL-27), that can cure established tumors and promote long-term antitumor immunity in murine pancreatic cancer tumor models.</p><p><strong>Methods: </strong>A novel oncolytic VV with deletion of the TK, N1L, and A41L genes, and expression of the red fluorescent protein (RFP) gene (VVL-TD-RFP) was constructed using CRISPR-Cas9-based homologous recombination. This virus was armed with IL-27, creating VVL-TD-IL-27. The characteristics of these viruses were evaluated <i>in vitro</i> using viral replication assays, cytotoxicity assays and ELISA. The antitumor effects of VVL-TD-IL-27 were evaluated using a variety of pancreatic cancer tumor models <i>in vivo</i>, and the mechanisms of antitumor effects were explored using flow cytometry, immunohistochemistry, ELISA and quantitative PCR.</p><p><strong>Results: </strong>VVL-TD-RFP cured 71.4% of tumor-bearing mice, compared with 14.3% of animals treated with VVLΔTKΔN1L that does not have an A41L gene deletion. Efficacy was mainly dependent on elevated dendritic cell (DC) populations, activation of DC, CD86⁺ DC, and CD8⁺ effector memory T cells in the TME. Efficacy was further enhanced by arming VVL-TD-RFP with IL-27, which resulted in a cure rate of 100% and promoted long-term antitumor immunity. VVL-TD-IL-27 treatment increased the proportion of CD8⁺ TEM and decreased the proportion of regulatory T cells and macrophages in tumor tissues. It also polarized macrophages to an M1 phenotype <i>in vivo</i>. Furthermore, IL-27 exhibits strong anti-angiogenic effects.</p><p><strong>Conclusions: </strong>VVL-TD-mIL-27 is a potential immunotherapy agent for the treatment of pancreatic cancer, and a clinical study of this virus is warranted.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067774/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143997739","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":"Spatial transcriptomics highlights B cells as key contributors to a complete and durable response to chemo-immunotherapy in a patient with resectable NSCLC.","authors":"Nicla Porciello, Filippo Gallina, Giuseppe Frisullo, Francesca Fusco, Lorenzo D'Ambrosio, Vittoria Balzano, Francesca De Nicola, Paolo Visca, Lorenza Landi, Federico Cappuzzo, Paola Nistico","doi":"10.1136/jitc-2025-011563","DOIUrl":"10.1136/jitc-2025-011563","url":null,"abstract":"<p><p>Neoadjuvant chemo-immunotherapy has significantly improved the treatment landscape for patients with ALK/EGFR wt resectable non-small cell lung cancer (NSCLC), offering novel opportunities for translational and clinical investigations. By leveraging deep molecular profiling through spatial transcriptomics integrated with single-cell RNA-sequencing from public atlases, and serum proteomic profiling, we report a case of a patient with resectable NSCLC and a solitary synchronous brain metastasis showing a complete pathologic response after chemo-immunotherapy, and a durable event-free survival. The deep profiling of the tumor immune microenvironment of both pre-treatment brain metastasis and post-treatment primary lung tumor tissues unveiled a key role of B lymphocytes at different maturation state, spanning from naïve to plasma cells, in mediating tumor eradication. Notably, the formation of several tertiary lymphoid structures in the regression bed of post-treatment primary tumor was observed, suggesting the in situ generation of high-affinity antibody and specific immune memory response. This multimodal approach paves the way for the discovery of novel biomarkers at both tissue and systemic levels, fostering improved patient stratification and guiding clinical decisions on post-surgical treatment escalation or de-escalation.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067772/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967521","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":"The cold immunological landscape of ATM-deficient cancers.","authors":"Sonali Sinha, Victor Ng, Ardijana Novaj, Yingjei Zhu, Shu Yazaki, Xin Pei, Fatemeh Derakhshan, Fresia Pareja, Jeremy Setton, Flavie Naulin, Manuel Beltrán-Visiedo, Ethan Shin, Ana Leda F Longhini, Rui Gardner, Jennifer Ma, Kevin Ma, Anne Roulston, Stephen Morris, Maria Koehler, Simon Powell, Ezra Rosen, Lorenzo Galluzzi, Jorge Reis-Filho, Atif Khan, Nadeem Riaz","doi":"10.1136/jitc-2024-010548","DOIUrl":"https://doi.org/10.1136/jitc-2024-010548","url":null,"abstract":"<p><strong>Background: </strong>Mutations in genes encoding DNA repair factors, which facilitate mismatch repair, homologous recombination, or DNA polymerase functions, are known to enhance tumor immunogenicity. Ataxia telangiectasia mutated (<i>ATM</i>) is a central regulator of DNA double-strand break repair and is frequently affected by somatic or germline mutations in various cancer types, including breast, prostate, pancreatic, and lung cancer. However, the consequences of <i>ATM</i> loss on tumor immunogenicity are poorly understood.</p><p><strong>Methods: </strong>We generated isogenic ATM-null models using CRISPR in murine triple-negative breast (4T1) and colorectal (CT26) cancer cell lines. ATM inactivation was confirmed by PCR and western blot. Immune cell infiltrates were assessed by flow cytometry and immunohistochemistry in both murine tumors and human samples from breast and lung cancers (via The Cancer Genome Atlas and institutional cohorts). In vivo, the impact of ATM loss on tumor growth and response to immune checkpoint blockade (anti-programmed cell death protein-1 (PD-1)) was evaluated. Furthermore, we compared the effects of different DNA-damaging agents-including an ATR inhibitor (RP-3500), a PARP inhibitor (olaparib), and the topoisomerase II inhibitor etoposide-on interferon-stimulated gene (ISG) expression and immune modulation.</p><p><strong>Results: </strong>We find that-in contrast to other DNA repair defects<i>-ATM</i> deficiency (1) fails to encourage immune effector cell infiltration into tumors, and (2) does not enable immune cell recruitment via synthetic lethality strategies in clinical trials, such as with ATR inhibition. Assessing various DNA-damaging agents in <i>Atm</i> null tumors revealed a differential activation of type I interferon (IFN) signaling, with etoposide, a topoisomerase II inhibitor, emerging as the strongest activator of ISG under these conditions. Yet, PD-1-targeted immune checkpoint blockade does not bolster the therapeutic activity of etoposide in <i>Atm</i>-null syngeneic tumor models, nor does it modify the tumor microenvironment, suggesting that type I IFN signaling alone is insufficient to overcome immunosuppression in immunologically cold <i>ATM</i> null neoplasms.</p><p><strong>Conclusions: </strong>ATM deficiency, while compromising DNA repair and enhancing sensitivity to radiation and ATR inhibition, does not increase tumor antigenicity or immunogenicity. Altogether, our results have important implications for the design of novel combination therapies for <i>ATM</i> null tumors and highlight the importance of antigenicity in the immunological consequences of defective DNA repair.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 5","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12067784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144010553","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}