Journal for Immunotherapy of Cancer最新文献

{"title":"Letter to the editor: radiomics signature for dynamic monitoring of tumor-inflamed microenvironment and immunotherapy response prediction.","authors":"Yuhao Dong, Shuixing Zhang","doi":"10.1136/jitc-2025-011778","DOIUrl":"10.1136/jitc-2025-011778","url":null,"abstract":"<p><p>We read with great interest the article by Bernatowicz <i>et al</i> Despite the promising findings, we would like to highlight several concerns regarding the methodology and interpretation of the results that warrant further discussion, including the stability of radiomic features across pan-cancer types, the optimal threshold for CT-TIME (tumor immune microenvironment) scores, the biological interpretability of radiomic models, and the survival tail effect of immunotherapy responses.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11873337/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531385","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":"T-cell immune checkpoint inhibition plus hypomethylation for locally advanced HER2-negative breast cancer: a phase 2 neoadjuvant window trial of decitabine and pembrolizumab followed by standard neoadjuvant chemotherapy.","authors":"Harry D Bear, Xiaoyan Deng, Dipankar Bandyopadhyay, Michael Idowu, Taylor M Jenkins, Maciej Kmieciak, Monique Williams, Giovanni Archer, Lindsey Gwaltney, Patrick Dillon, Daniel Flora, Daniel Stover, Andrew S Poklepovic, Mary Hackney, Masey Ross, Hetal Vachhani, Raphael Louie, Kandace P McGuire, Amelia Grover, Tasnim Rahman, Amber Hendrix","doi":"10.1136/jitc-2024-010294","DOIUrl":"10.1136/jitc-2024-010294","url":null,"abstract":"<p><strong>Background: </strong>Higher levels of tumor-infiltrating lymphocytes (TILs) in breast cancers are associated with increased likelihood of pathologic complete response (pCR) to chemotherapy. DNA methyltransferase inhibitors (DNMTi) can augment immune responses to cancers, decreasing myeloid-derived suppressor cells (MDSCs) and increasing T lymphocyte responsiveness. We have shown that the DNMTi decitabine augments the effectiveness of immunotherapy using murine triple-negative breast cancer (TNBC) models. The primary objective was to determine whether DNMTi+immune checkpoint blockade would increase stromal TIL (sTIL) in primary breast cancers before neoadjuvant chemotherapy (NCT).</p><p><strong>Methods: </strong>In a phase 2 study (NCT02957968), patients with human epidermal growth factor receptor 2-negative breast cancer received window immunotherapy-decitabine (15 mg/m²×4 doses over 5 days) followed by 2 doses of pembrolizumab (200 mg, 2 weeks apart)-before starting NCT. Biopsies before and after window immunotherapy quantified TILs and programmed death-ligand 1 (PD-L1) expression. Patients proceeded to NCT and tumor resection per standard of care. Mid-study, results of the KEYNOTE 522 trial led to patients with TNBC receiving additional pembrolizumab concurrently with standard NCT and in the adjuvant setting.</p><p><strong>Results: </strong>46 patients (median age 54.5 years, range 28-72; 71.7% white, 28.3% black; 100% female) were treated. 21 patients had TNBC and received neither neoadjuvant pembrolizumab concurrently with NCT nor adjuvant pembrolizumab (Cohort A), 7 patients had TNBC and did receive concurrent and/or adjuvant pembrolizumab (Cohort A2), and 18 patients were estrogen receptor positive and/or progesterone receptor positive and received neither concurrent nor adjuvant pembrolizumab (Cohort B). Blood samples collected after decitabine administration before pembrolizumab showed a 59% decrease (p<0.01) in monocytic MDSCs compared with baseline. 38 patients had paired biopsies for sTIL and 37 for PD-L1 evaluation. Cohorts A/A2 experienced an sTIL increase of 6.1% (p<0.008); Cohort B experienced an sTIL increase of 8.3% (p=0.006). PD-L1 expression increased by 73.9% (p<0.01). 14 of 43 patients (32.6%) who proceeded to resection achieved pCR (n=11 of 27 (40.1%) in Cohorts A/A2 and n=3 of 16 (18.8%) in Cohort B). The most frequently reported immune-related adverse events were adrenal insufficiency (AI) (n=6, 13.0%), maculopapular rash (n=3, 6.5%), and hypothyroidism (n=3, 6.5%). Five of the six AI instances were at least partially attributable to hypophysitis/pituitary dysfunction, and one remains uncertain.</p><p><strong>Conclusions: </strong>Treatment in the pre-neoadjuvant window with decitabine and pembrolizumab could sensitize breast cancers to standard NCT by recruitment of TILs to the tumor tissue. The treatment was well-tolerated.</p><p><strong>Trial registration number: </strong>NCT02957968.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11873355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143531393","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":"Enhanced thrombopoiesis supplies PD-L1 to circulating immune cells via the generation of PD-L1-expressing platelets in patients with lung cancer.","authors":"Sung-Woo Lee, Saei Jeong, Young Ju Kim, Jeong Eun Noh, Kyung Na Rho, Hee-Ok Kim, Hyun-Ju Cho, Deok Hwan Yang, Eu Chang Hwang, Woo Kyun Bae, Sook Jung Yun, Ju Sik Yun, Cheol-Kyu Park, In-Jae Oh, Jae-Ho Cho","doi":"10.1136/jitc-2024-010193","DOIUrl":"10.1136/jitc-2024-010193","url":null,"abstract":"<p><strong>Background: </strong>The increased expression of programmed cell death ligand 1 (PD-L1) on a subset of immune cells in the peripheral blood has been frequently observed in patients with cancer, suggesting a relationship with PD-L1 expression in tumor tissues. In this study, we investigated the mechanisms underlying PD-L1 expression on various types of immune cells in the peripheral blood of patients with cancer.</p><p><strong>Methods: </strong>PD-L1 expression on various immune cell populations was analyzed in peripheral blood mononuclear cells of 112 patients with non-small cell lung cancer (NSCLC) using flow cytometry. A mouse model of X-ray-induced acute thrombocytopenia was used to investigate the relationship between thrombopoiesis and PD-L1-expressing platelet generation. The clinical significance of PD-L1-expressing platelets was analyzed in a cohort of patients with stage IV NSCLC who received a combination of anti-programmed cell death 1 (PD-1) therapy and chemotherapy.</p><p><strong>Results: </strong>All immune cell populations, including monocytes, T cells, B cells, and NK cells, showed higher PD-L1 expression in patients with cancer than in healthy controls. However, this increased frequency of PD-L1-expressing cells was not attributed to the expression of the cells themselves. Instead, it was entirely dependent on the direct interaction of the cells with PD-L1-expressing platelets. Notably, the platelet-dependent acquisition of PD-L1 on circulating immune cells of patients with lung cancer was observed in various other cancer types and was mechanistically associated with a surge in thrombopoiesis, resulting in the increased production of PD-L1-expressing reticulated platelets. Clinically, patients with enhanced thrombopoiesis and concurrently high PD-L1-expressing platelets exhibited a better response to anti-PD-1 therapy.</p><p><strong>Conclusions: </strong>These findings highlight the role of tumor-associated thrombopoiesis in generating PD-L1-expressing platelets that may serve as a resource for PD-L1-positive cells in the circulation and act as a predictive biomarker for anti-PD-1/PD-L1 therapy.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515547","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":"Neutrophil extracellular traps impede cancer metastatic seeding via protease-activated receptor 2-mediated downregulation of phagocytic checkpoint CD24.","authors":"Yu Liu, Jianhui Ma, Yiming Ma, Bing-Zhi Wang, Yinong Wang, Junhu Yuan, Fanyu Zhang, Xinhua Zhao, Kun Chen, Xiaoli Zhang, Hongying Wang","doi":"10.1136/jitc-2024-010813","DOIUrl":"10.1136/jitc-2024-010813","url":null,"abstract":"<p><strong>Background: </strong>Phagocytic clearance by macrophages represents a critical immune surveillance mechanism in cancer liver metastasis. Neutrophils, the most abundant immune cells encountered by cancer cells in circulation, play key roles in metastasis through neutrophil extracellular traps (NETs). Although NETs promote macrophage phagocytosis during infection, whether they regulate phagocytosis during cancer metastasis is unknown. The present study aimed to explore the roles of NETs in regulating macrophage phagocytosis during the seeding process of liver metastasis and the mechanisms underlying the roles.</p><p><strong>Methods: </strong>A lipopolysaccharide-induced NET model was applied to study the role of NETs on colorectal cancer (CRC) liver metastasis. The neutrophils isolated from human peripheral blood were stimulated with PMA to release NETs, which were collected and added to the cultures of different CRC cell lines for in vitro studies. Macrophage phagocytosis was assessed with flow cytometry in vitro and in vivo. RNA-seq and microRNA array analyses were performed to identify key pathways regulated by NETs and downstream key molecules. The macrophage phenotypes were evaluated using immunohistochemistry, flow cytometry, and cytokine and chemokine arrays.</p><p><strong>Results: </strong>NETs promote macrophage phagocytosis both in vitro and in vivo. Neutrophil elastase (NE), which was able to inactivate the canonical signal of protease-activated receptor 2 (PAR2), downregulated the phagocytotic checkpoint CD24. Notably, PAR2 deficiency imitated the effect of NETs on phagocytosis and CD24. Mechanistic studies indicated that inhibiting PAR2 expression upregulated miR-34a and miR-146a and downregulated CD24 in cancer cells. In addition, PAR2 depletion enhanced the recruitment and M1 polarization of macrophages by upregulating CSF-1 and CXCL1. The correlation of NETs/NE and CD24 was corroborated using human CRC specimens. Furthermore, PAR2 blockade combined with an anti-EGFR antibody (cetuximab (CTX)) synergistically enhanced the phagocytic ability of macrophages and suppressed liver metastasis in vivo.</p><p><strong>Conclusions: </strong>NET-derived elastase inactivated PAR2 canonical signaling and promoted phagocytosis by downregulating CD24, which functions as a phagocytotic checkpoint in CRC liver metastasis. Thus, PAR2 inhibitors combined with CTX may serve as a novel therapeutic strategy against advanced CRC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515478","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":"CD47 as a potential predictive biomarker in colorectal cancer.","authors":"Justin Stebbing, Andrea Bullock","doi":"10.1136/jitc-2024-011142","DOIUrl":"10.1136/jitc-2024-011142","url":null,"abstract":"<p><p>In this week's Journal for ImmunoTherapy for Cancer, Arai and colleagues analyzed next-generation sequencing data for DNA and RNA from 14,287 patients with colorectal cancer (CRC) categorized by median CD47 expression level, and showed that CD47, a key component of innate immunity in deflecting phagocytosis, is associated with molecular subtypes of CRC, cell damage-associated molecular pattern-related genes, major oncogenic pathways, and adaptive immune checkpoint genes. Taken together, they concluded that CD47 expression is associated with activation of oncogenic pathways and an immune-engaged tumor microenvironment. Clinical outcomes data also demonstrated that high CD47 is associated with prolonged survival in patients treated with antiangiogenic and checkpoint inhibitor therapy. Biomarker studies such as this will enable broader application of immuno-oncology to patients with CRC and other malignancies.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"13 2","pages":""},"PeriodicalIF":10.3,"publicationDate":"2025-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11865770/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515800","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":"Effector T cells under hypoxia have an altered transcriptome similar to tumor-stressed T cells found in non-responsive melanoma patients.","authors":"Mate Z Nagy, Lourdes B Plaza-Rojas, Justin C Boucher, Elena Kostenko, Anna L Austin, Ahmad A Tarhini, Zhihua Chen, Dongliang Du, Awino Maureiq E Ojwang', Joshua Davis, Alyssa Obermayer, Katarzyna A Rejniak, Timothy I Shaw, Jose A Guevara-Patino","doi":"10.1136/jitc-2024-010153","DOIUrl":"https://doi.org/10.1136/jitc-2024-010153","url":null,"abstract":"<p><strong>Background: </strong>In the tumor microenvironment (TME), hypoxia stands as a significant factor that modulates immune responses, especially those driven by T cells. As T cell-based therapies often fail to work in solid tumors, this study aims to investigate the effects of hypoxia on T cell topo-distribution in the TME, gene expression association with T cell states, and clinical responses in melanoma.</p><p><strong>Methods: </strong>To generate detailed information on tumor oxygenation and T cell accessibility, we used mathematical modeling of human melanoma tissue microarrays that incorporate oxygen supply from vessels, intratumoral diffusion, and cellular uptake. We created tumor maps and derived plots showing the fraction of CD4 and CD8 T cells against the distance to the nearest vessel and oxygen pressure. To assess their function and transcriptional changes caused by hypoxia, effector T cells were generated and cultured under hypoxia (0.5% oxygen) or normoxia (21% oxygen). The T cell hypoxia-transcriptional signature was compared against datasets from msigDB, iATLAS (clinical trials of melanoma patients treated with immune checkpoint inhibitors (ICIs)), ORIEN AVATAR (real-world melanoma patients treated with ICIs), and a single-cell atlas of tumor-infiltrating lymphocytes.</p><p><strong>Results: </strong>We made three specific observations: (1) in melanoma T cells preferentially accumulated in oxygenated areas close to blood vessels (50-100 µm from the vasculature in the regions of high oxygen availability) but not in hypoxic areas far from blood vessels. (2) Our analysis confirmed that under hypoxia, T cell functions were significantly reduced compared with normoxic conditions and accompanied by a unique gene signature. Furthermore, this hypoxic gene signature was prevalent in resting and non-activated T cells. Notably and clinically relevant, the hypoxic T cell gene set was found to correlate with reduced overall survival and reduced progression-free survival in melanoma patients, which was more pronounced in non-responder patients undergoing ICI therapy. (3) Finally, compared with a single-cell atlas of tumor-infiltrating T cells, our hypoxia signature aligned with a population of cells at a state termed stress response state (T_STR).</p><p><strong>Conclusions: </strong>Our study highlights the critical role of hypoxia in shaping T cell distribution and its correlation with clinical outcomes in melanoma. We revealed a preferential accumulation of T cells in oxygenated areas. Moreover, hypoxic T cells develop a distinct hypoxic gene signature prevalent in resting, non-activated T cells and T_STR that was also associated with poorer outcomes, particularly pronounced among non-responders to ICIs.</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":"143515546","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":"Fc-competent TIGITx4-1BB bispecific antibody exerts potent long-lasting antitumor activity by potentiating CD8⁺ T cell activity and Fcγ receptor-mediated modulation of the tumor microenvironment.","authors":"Wonjun Son, Yangsoon Lee, Yelim Park, Kyeong-Su Park, Sora Kim, Hyunseong Youn, Arim Seo, Byungje Sung, Sang Hoon Lee, Jonghwa Won","doi":"10.1136/jitc-2024-010728","DOIUrl":"https://doi.org/10.1136/jitc-2024-010728","url":null,"abstract":"<p><strong>Background: </strong>TIGIT was identified as a target immune checkpoint for overcoming resistance to PD-(L)1-blocking antibodies. However, the clinical efficacies of TIGIT antibodies were moderate in monotherapy and mixed in combination with PD-(L)1 antibodies. 4-1BB, a strong inducible costimulatory receptor, is another attractive target in antitumor therapeutics. This study investigated whether ABL112, an Fc-competent bispecific antibody targeting TIGIT and 4-1BB (TIGITx4-1BB), would enhance antitumor activity via Fcγ receptor (FcγR)-mediated macrophage activation and antibody-dependent cell-mediated functions.</p><p><strong>Methods: </strong>TIGIT-dependent 4-1BB activation and TIGIT-blocking activity were assessed using reporter Jurkat T cell lines expressing 4-1BB and TIGIT, respectively. In vivo antitumor activity was confirmed in h4-1BB knock-in mice. The main immune cell subsets associated with the antitumor activity of ABL112 were identified using antibodies for depleting specific immune cell subtypes or FcγR-blocking antibodies. The effects of a combined pembrolizumab or atezolizumab treatment with ABL112 were assessed in two mouse models with different genetic backgrounds. Statistical analysis was performed using one-way or two-way analysis of variance (ANOVA) with Dunnett's multiple-comparison test or one-way ANOVA with Fisher's multiple-comparison test.</p><p><strong>Results: </strong>ABL112 restored T cell activity by blocking TIGIT-CD155 interactions, based on a TIGIT blockade reporter assay. ABL112, an Fc-competent TIGITx4-1BB bispecific antibody, showed strong FcγRI-dependent 4-1BB activation along with TIGIT-dependent 4-1BB activation. In H22 tumor models expressing high levels of endogenous CD155, both ABL112 and parent TIGIT single-domain Ab showed potent tumor-suppressive activity; however, only ABL112 exerted long-lasting antitumor activity. ABL112 induced a marked decrease in Treg numbers, while augmenting the absolute number of CD8⁺ T cells and proportion of CD226⁺ CD8⁺ T cells. The expressions of CXCL10, CXCL11, IFN-γ, and TNF-α increased, indicating myeloid cell activation and potential modification of the tumor microenvironment to an inflammatory phenotype. ABL112 not only showed outstanding antitumor activity as a monotherapy, but also showed synergistic effects with PD-(L)1 mAb compared with the combined TIGIT-PD-(L)1 mAb treatments.</p><p><strong>Conclusions: </strong>Through multiple mechanisms of action, ABL112 exerted potent tumor-killing activity and immune memory response alone or in combination with anti-PD-(L)1 therapies, representing a promising new cancer treatment strategy.</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":"143515558","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":"Targeting mesothelin-CD24 axis repolarizes tumor-associated macrophages to potentiate PD-1 blockade therapy in high-grade serous ovarian cancer.","authors":"Yujing Zhong, Yiying Wang, Chenyang Wang, Kankan Cao, Xueling Wang, Xuyao Xu, Moran Yang, Guodong Zhang, Haiou Liu, Jiaqi Lu","doi":"10.1136/jitc-2024-011230","DOIUrl":"10.1136/jitc-2024-011230","url":null,"abstract":"<p><strong>Background: </strong>High-grade serous ovarian cancer (HGSOC) is a highly aggressive malignancy marked by an immunosuppressive tumor microenvironment that hinders effective immune responses. A key feature of this environment is the extensive infiltration of myeloid cells, which contributes to immune evasion. This study explored how mesothelin (MSLN), a tumor-associated antigen, modulates the expression of CD24, an emerging target for immune modulation, and its role in promoting immune evasion in HGSOC. Understanding these underlying mechanisms is crucial for enhancing the efficacy of immune checkpoint blockade (ICB) therapies and improving outcomes in patients with HGSOC.</p><p><strong>Methods: </strong>We analyzed the expression of MSLN in HGSOC samples and examined its correlation with clinical outcome. In vitro and in vivo models were used to explore how MSLN influences CD24 expression and the polarization of tumor-associated macrophages (TAMs). We also investigated the role of MSLN in the activation of Wnt/β-catenin signaling and its impact on T-cell function and antitumor immunity. The effects of <i>Msln</i> knockdown on CD24 expression and the response to anti-programmed cell death protein-1 (PD-1) therapy were evaluated in syngeneic mouse models.</p><p><strong>Results: </strong>MSLN expression was found to be significantly elevated in HGSOC, with high MSLN levels correlating with poor prognosis and resistance to ICB. MSLN upregulated CD24 and promoted the protumorigenic polarization of TAMs, contributing to T-cell dysfunction. Mechanistically, MSLN activated Wnt/β-catenin signaling, which in turn enhanced CD24 expression. This activation forms a positive feedback loop that further promotes MSLN transcription. In contrast, <i>Msln</i> knockdown reduced CD24 expression, relieved cytotoxic T-cell suppression, and significantly improved the efficacy of anti-PD-1 therapy in syngeneic models.</p><p><strong>Conclusions: </strong>This study elucidates the critical role of MSLN in immune evasion in HGSOC and its underlying mechanisms. Targeting MSLN in combination with ICB is a promising strategy to enhance the efficacy of immunotherapy and improve patient outcomes in HGSOC.</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/PMC11873354/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515625","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":"Immunological biomarkers of response and resistance to treatment with cabozantinib and nivolumab in recurrent endometrial cancer.","authors":"Vladimir Roudko, Diane Marie Del Valle, Emir Radkevich, Geoffrey Kelly, Xie Hui, Manishkumar Patel, Edgar Gonzalez-Kozlova, Kevin Tuballes, Howard Streicher, Swati Atale, Lisa Wang, Benito CzinCzin, Seunghee Kim-Schulze, Ignacio I Wistuba, Cara L Haymaker, Gheath Al-Atrash, Ganiraju Manyam, Jianjun Zhang, Ryan Thompson, Mayte Suarez-Farinas, Stephanie Lheureux, Sacha Gnjatic","doi":"10.1136/jitc-2024-010541","DOIUrl":"10.1136/jitc-2024-010541","url":null,"abstract":"<p><strong>Background: </strong>Antiangiogenics combined with immune checkpoint blockade have become standard of care for recurrent endometrial cancer after standard platinum-based chemotherapy. To dissect mechanisms and define biomarkers associated with clinical outcomes to these combinations, we applied multidimensional immune monitoring to peripheral blood specimens collected from a randomized phase 2 trial of nivolumab with or without cabozantinib in 75 evaluable patients with recurrent endometrial cancer (NCI ETCTN 10104, NCT03367741). This trial demonstrated superiority of the combination to nivolumab alone.</p><p><strong>Methods and results: </strong>Using Olink proteomics, mass cytometry, tumor antigen-specific ELISA, and whole exome tumor sequencing, we identified longitudinal immune signatures specific to cabozantinib use, including an increase in plasma HO-1 and reduction in plasma vascular endothelial growth factor receptor 2, interleukin-12, and circulating plasmacytoid dendritic cells. Prior exposure to immunotherapy and carcinosarcoma histology had no adverse impact on clinical benefit or biomarkers, and copy-number high tumors were associated with increased plasma granzymes on combination treatment. Higher baseline plasma levels of myeloid-related markers (chemokine ligand 23/CCL23, colony-stimulating factor-1/macrophage colony-stimulating factor/CSF1) were associated with poor overall and progression-free survival, and lack of clinical benefit (defined as progressive or stable disease <6 months) following combination treatment (Kaplan-Meier, multivariate Cox, false discover rate <0.05). Patients with favorable outcomes had higher levels of activated T-cell markers (plasma ICOS-L, CD28) and exhibited spontaneous autoantibody titers to tumor antigen NY-ESO-1. Patients experiencing severe adverse events from the combination therapy had higher baseline levels of neutrophil-derived markers (CXCL1).</p><p><strong>Conclusions: </strong>Overall, this study highlights potential resistance and response mechanisms to nivolumab+cabozantinib and suggests prioritizing combination treatment in patients with activated T-cell immunogenicity profiles while exploring future combinatorial therapies targeting myeloid populations to overcome resistance.</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/PMC11865721/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515570","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":"Effect of prior and first-line immunotherapy on baseline immune biomarkers and modulation of the tumor microenvironment in response to nivolumab and relatlimab combination therapy in patients with melanoma from RELATIVITY-020.","authors":"Paolo A Ascierto, Hao Tang, Sonia Dolfi, Marta Nyakas, Inge Marie Svane, Eva Muñoz-Couselo, Jean Jacques Grob, Carlos Alberto Gomez-Roca, Vanna Chiarion-Sileni, Katriina Peltola, James Larkin, Ignacio Melero, Margaret Callahan, Reinhard Dummer, Patrick Djidel, Deepti Warad, Diane Reusser-Wolf, Evan J Lipson, Charlie Garnett-Benson","doi":"10.1136/jitc-2024-009773","DOIUrl":"https://doi.org/10.1136/jitc-2024-009773","url":null,"abstract":"<p><strong>Background: </strong>Some patients with melanoma experience disease progression during immunotherapy (IO) and may benefit from novel combinations of immune checkpoint inhibitors (ICIs). We report results from exploratory biomarker analyses to characterize the responses of patients with advanced melanoma to treatment with nivolumab (anti-programmed cell death-1 (PD-1)) and relatlimab (anti-lymphocyte-activation gene 3 (LAG-3)) combination therapy in RELATIVITY-020 (NCT01968109).</p><p><strong>Methods: </strong>Tumor biopsies collected at baseline and ≤4 weeks after treatment initiation were evaluated for % LAG-3-positive and % CD8-positive immune cells and % programmed death-ligand 1 (PD-L1) expression on tumor cells. Baseline biomarker expression was compared among patients with IO-refractory melanoma based on last prior therapy and IO-resistance type, and between patients with IO-refractory and IO-naïve melanoma. Change in biomarker expression after treatment was evaluated in patients with IO-refractory and IO-naïve melanoma. Immune-related gene expression was compared among resistance groups and by the last prior treatment.</p><p><strong>Results: </strong>Among patients with IO-refractory melanoma (N=505), elevated baseline LAG-3, PD-L1, and CD8 expression (p≤0.01, p≤0.05, p≤0.001, respectively) was observed in patients whose last prior therapy was IO versus non-IO, and in those who responded (complete/partial per Response Evaluation Criteria in Solid Tumors V.1.1) to nivolumab and relatlimab combination therapy versus those who did not (stable/progressive disease). Inflammation-related gene expression was significantly higher (p<0.05) in patients with secondary versus primary resistance to prior IO treatment, and in those whose last prior therapy was IO versus non-IO. IO-refractory patients whose tumors responded to nivolumab and relatlimab combination therapy had higher inflammation-related gene expression than non-responders (p<0.05); proliferation and hypoxia-related gene expression were enriched in non-responders. During treatment with nivolumab and relatlimab combination therapy, LAG-3 expression increased significantly in patients with IO-refractory (p≤0.01) and IO-naïve melanoma (p≤0.001), and PD-L1 and CD8 increased significantly (p≤0.01 and p≤0.05, respectively) in patients with IO-naïve melanoma.</p><p><strong>Conclusions: </strong>Nivolumab and relatlimab combination therapy can modulate the tumor microenvironment in patients with both IO-refractory and IO-naïve melanoma. Further research is needed to identify patients who will most benefit from anti-LAG-3/PD-(L)1 agents, and to elucidate the mechanisms of action of, and resistance to, this combination therapy in patients with advanced melanoma.</p><p><strong>Trial registration number: </strong>NCT01968109.</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":"143515545","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}