Journal for Immunotherapy of Cancer最新文献

{"title":"In situ endoscopic photodynamic therapy combined with immature DC vaccination induces a robust T cell response against peritoneal carcinomatosis.","authors":"Charline Degavre, Anouk Lepez, Sebastien Ibanez, Clémence François, Katarzyna Głowacka, Céline Guilbaud, Florine Laloux-Morris, Hrag Esfahani, Davide Brusa, Caroline Bouzin, Olivier Feron","doi":"10.1136/jitc-2024-009752","DOIUrl":"10.1136/jitc-2024-009752","url":null,"abstract":"<p><strong>Background: </strong>Immunogenic cell death (ICD) and ferroptosis have recently emerged as key factors in the anticancer immune response. Among the treatments able to induce ICD and the associated release of danger signals is photodynamic therapy (PDT). Ferroptosis for its part results from lipid peroxidation and is induced by CD8⁺ T cells to kill nearby cancer cells on IFN-γ production. We aimed to combine the two concepts, that is, to evaluate whether the strong pro-oxidant effects of PDT may promote ferroptosis and antigen release and to develop a procedure for in situ PDT to prepare the soil for highly endocytotic immature dendritic cell (iDC) adoptive transfer. This approach was implemented for managing peritoneal carcinomatosis, a lesion often associated with poor outcomes.</p><p><strong>Methods: </strong>We used three-dimensional (3D) heterotypic spheroids made of cancer cells, exposed them to a white light-activated OR141 photosensitizer (PS), and subsequently complexified them by adding iDC and naive lymphocytes. We next used a model of mouse peritoneal carcinomatosis and administered PDT using laparoscopy to locally induce photoactivation using the endoscope light. The immune response following adoptive transfer of iDC was tracked both in vivo and ex vivo using isolated immune cells from in situ vaccinated mice.</p><p><strong>Results: </strong>Cancer cells undergoing PDT-induced cell death significantly increased ICD markers and the infiltration of iDCs in spheroids, relying on ferroptosis. These actions induced the sequential activation of CD8⁺ and CD4⁺ T cells as revealed by a significant spheroid 3D structure deterioration and, remarkably, were not recapitulated by conventional ferroptosis inducer RSL3. Using LED light from an endoscope for in situ photoactivation of PS enabled us to apply the vaccination modality in mice with peritoneal tumors. Consecutive intraperitoneal injection of iDCs resulted in delayed tumor growth, increased survival rates, and prevented tumor relapse on rechallenge. CD8⁺ T cell response was supported by depletion experiments, nodal detection of early activated T cells, and ex vivo T cell-induced cytotoxicity toward spheroids.</p><p><strong>Conclusions: </strong>The combination of in situ PDT locally delivered by an endoscope light and iDC administration induces a durable memory immune response against peritoneal carcinomatosis thereby opening new perspectives for the treatment of a life-threatening condition.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 11","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552574/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cancer-associated fibroblasts shape early myeloid cell response to chemotherapy-induced immunogenic signals in next generation tumor organoid cultures.","authors":"Julijan Kabiljo, Anna Theophil, Jakob Homola, Annalena F Renner, Nathalie Stürzenbecher, Daphni Ammon, Rebecca Zirnbauer, Simone Stang, Loan Tran, Johannes Laengle, Askin Kulu, Anna Chen, Markus Fabits, Velina S Atanasova, Oliver Pusch, Wolfgang Weninger, Henning Walczak, Dietmar Herndler Brandstetter, Gerda Egger, Helmut Dolznig, Anna Kusienicka, Matthias Farlik, Michael Bergmann","doi":"10.1136/jitc-2024-009494","DOIUrl":"10.1136/jitc-2024-009494","url":null,"abstract":"<p><strong>Background: </strong>Patient-derived colorectal cancer (CRC) organoids (PDOs) solely consisting of malignant cells led to major advances in the understanding of cancer treatments. Yet, a major limitation is the absence of cells from the tumor microenvironment, thereby prohibiting potential investigation of treatment responses on immune and structural cells. Currently there are sparse reports describing the interaction of PDOs, cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) in complex primary co-culture assay systems.</p><p><strong>Methods: </strong>Primary PDOs and patient matched CAF cultures were generated from surgical resections. Co-culture systems of PDOs, CAFs and monocytic myeloid cells were set up to recapitulate features seen in patient tumors. Single-cell transcriptomics and flow cytometry was used to show effects of culture systems on TAM populations in the co-culture assays under chemotherapeutic and oncolytic viral treatment.</p><p><strong>Results: </strong>In contrast to co-cultures of tumor cells and monocytes, CAF/monocyte co-cultures and CAF/monocyte/tumor cell triple cultures resulted in a partial differentiation into macrophages and a phenotypic switch, characterized by the expression of major immunosuppressive markers comparable to TAMs in CRC. Oxaliplatin and 5-fluorouracil, the standard-of-care chemotherapy for CRC, induced polarization of macrophages to a pro-inflammatory phenotype comparable to the immunogenic effects of treatment with an oncolytic virus. Monitoring phagocytosis as a functional proxy to macrophage activation and subsequent onset of an immune response, revealed that chemotherapy-induced cell death, but not virus-mediated cell death, is necessary to induce phagocytosis of CRC cells. Moreover, CAFs enhanced the phagocytic activity in chemotherapy treated CRC triple cultures.</p><p><strong>Conclusions: </strong>Primary CAF-containing triple cultures successfully model TAM-like phenotypes <i>ex vivo</i> and allow the assessment of their functional and phenotypic changes in response to treatments following a precision medicine approach.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 11","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535717/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582947","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":"Multicenter validation of an RNA-based assay to predict anti-PD-1 disease control in patients with recurrent or metastatic head and neck squamous cell carcinoma: the PREDAPT study.","authors":"Kevin C Flanagan, Jon Earls, Jeffrey Hiken, Rachel L Wellinghoff, Michelle M Ponder, Howard L McLeod, William H Westra, Vera Vavinskaya, Leisa Sutton, Ida Deichaite, Orlan K Macdonald, Karim Welaya, James Wade, Georges Azzi, Andrew W Pippas, Jennifer Slim, Bruce Bank, Xingwei Sui, Steven E Kossman, Todd D Shenkenberg, Warren L Alexander, Katharine A Price, Jessica Ley, David N Messina, Jarret I Glasscock, A Dimitrios Colevas, Ezra E W Cohen, Douglas Adkins, Eric J Duncavage","doi":"10.1136/jitc-2024-009573","DOIUrl":"10.1136/jitc-2024-009573","url":null,"abstract":"<p><strong>Background: </strong>Despite advances in cancer care and detection, >65% of patients with squamous cell cancer of the head and neck (HNSCC) will develop recurrent and/or metastatic disease. The prognosis for these patients is poor with a 5-year overall survival of 39%. Recent treatment advances in immunotherapy, including immune checkpoint inhibitors like pembrolizumab and nivolumab, have resulted in clinical benefit in a subset of patients. There is a critical clinical need to identify patients who benefit from these antiprogrammed cell death protein 1 (anti-PD-1) immune checkpoint inhibitors.</p><p><strong>Methods: </strong>Here, we report findings from a multicenter observational study, PREDicting immunotherapy efficacy from Analysis of Pre-treatment Tumor biopsies (PREDAPT), conducted across 17 US healthcare systems. PREDAPT aimed to validate OncoPrism-HNSCC, a clinical biomarker assay predictive of disease control in patients with recurrent or metastatic HNSCC treated with anti-PD-1 immune checkpoint inhibitors as a single agent (monotherapy) and in combination with chemotherapy (chemo-immunotherapy). The test used RNA-sequencing data and machine learning models to score each patient and place them into groups of low, medium, or high.</p><p><strong>Results: </strong>The OncoPrism-HNSCC prediction significantly correlated with disease control in both the monotherapy cohort (n=62, p=0.004) and the chemo-immunotherapy cohort (n=50, p=0.01). OncoPrism-HNSCC also significantly predicted progression-free survival in both cohorts (p=0.015 and p=0.037, respectively). OncoPrism-HNSCC had more than threefold higher specificity than programmed death-ligand 1 combined positive score and nearly fourfold higher sensitivity than tumor mutational burden for predicting disease control.</p><p><strong>Conclusions: </strong>Here, we demonstrate the clinical validity of the OncoPrism-HNSCC assay in identifying patients with disease control in response to anti-PD-1 immune checkpoint inhibitors.</p><p><strong>Trial registration number: </strong>NCT04510129.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 11","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566470","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":"Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study).","authors":"Hirokazu Shoji, Chie Kudo-Saito, Kengo Nagashima, Hiroshi Imazeki, Kai Tsugaru, Naoki Takahashi, Takeshi Kawakami, Yusuke Amanuma, Takeru Wakatsuki, Naohiro Okano, Yukiya Narita, Yoshiyuki Yamamoto, Rika Kizawa, Kei Muro, Kazunori Aoki, Narikazu Boku","doi":"10.1136/jitc-2024-010174","DOIUrl":"10.1136/jitc-2024-010174","url":null,"abstract":"<p><strong>Background: </strong>Gastric cancer (GC) is one of the most common and deadly malignant diseases worldwide. Despite revolutionary advances, the therapeutic efficacy of anti-PD1/PDL1 monoclonal antibodies in advanced GC is still low due to the emergence of innate and acquired resistance to treatment. Myeloid cells represent the majority of human immune cells. Therefore, their increase, decrease, and abnormality could have a significant impact on the patient's immune system and the progression of cancer, and reprogramming, inhibiting, and eliminating the tumor-supportive types may improve the immunological situation and efficacy of immunotherapy. However, the significance of myeloid cells in anti-PD1/PDL1 therapy remains unclear in GC. In the WJOG10417GTR study on GC, we sought to identify myeloid determinants that could predict anti-PD1 therapeutic efficacy and also serve as potential therapeutic targets.</p><p><strong>Methods: </strong>We collected tumor tissues and peripheral blood from 96 patients with advanced GC before and 1 month after anti-PD1 nivolumab monotherapy, and the isolated whole leucocytes were analyzed by flow cytometry for various immune cell populations, including many myeloid subsets. Then, the relationship between the cellular levels and progression-free survival (PFS) or overall survival (OS) was statistically analyzed.</p><p><strong>Results: </strong>We found that high levels of several myeloid subsets expressing molecules that have been targeted in drug discovery but not yet approved for clinical use were significantly associated with shorter PFS/OS as compared with low levels: PDL1⁺ and CTLA4⁺ myeloid subsets within tumors at baseline, PDL1⁺, B7H3⁺ and CD115⁺ myeloid subsets in peripheral blood at baseline, and LAG3⁺, CD155⁺ and CD115⁺ myeloid subsets in peripheral blood at post-treatment.</p><p><strong>Conclusions: </strong>This study revealed that these myeloid subsets are significant risk factors in nivolumab therapy for advanced GC. Targeting them may be useful as diagnostic biomarkers to predict potential anti-PD1 therapeutic efficacy, and also as therapeutic targets for accelerating the development of new drugs to improve clinical outcomes in immunotherapy for GC.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 11","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535716/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566506","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":"Reporting of late-onset immune-related adverse events with immune checkpoint inhibitors in VigiBase.","authors":"Roberta Noseda, Francesca Bedussi, Valentina Giunchi, Michele Fusaroli, Emanuel Raschi, Alessandro Ceschi","doi":"10.1136/jitc-2024-009902","DOIUrl":"10.1136/jitc-2024-009902","url":null,"abstract":"<p><strong>Background: </strong>To date, evidence on late-onset immune-related adverse events (irAEs) with immune checkpoint inhibitors (ICIs) is limited to a small number of clinical cases. This study aimed to identify drug- and patient-related characteristics potentially associated with the reporting of late-onset irAEs with ICIs in VigiBase, the WHO global database of individual case safety reports (ICSRs).</p><p><strong>Methods: </strong>Observational study comparing deduplicated ICSRs with ICIs reporting late-onset irAEs (occurred >90 days after ICI discontinuation) versus ICSRs with ICIs not reporting late-onset irAEs, collected in VigiBase from 2011 to December 31, 2022. Logistic regression was used to model the relationship between drug-related and patient-related characteristics of ICSRs and the reporting of late-onset irAEs. Significance was determined for variables with the lower bound of the 95% CI of the reporting OR (ROR) higher than 1 and a p value <0.05.</p><p><strong>Results: </strong>The study population consisted of 6006 ICSRs with ICI-related irAEs (4574, 76.2%, originated from Europe; 3900, 64.9%, involved males; median patient age was 67 years, IQR 59-74 years). Of these, 344 (5.7%) ICSRs reported a total of 388 late-onset irAEs, among which the most frequent were thyroiditis (n=45), pneumonitis (n=37), interstitial lung disease (n=25), hepatitis (n=23) and vitiligo (n=19). Median time to onset since ICI discontinuation was 167 days (IQR 115-294 days), with negligible proportion (3.2%) of co-reported antineoplastic agents during the discontinuation period. Logistic regression models showed disproportionate reporting of late-onset irAEs with ICI combination therapy (ROR 2.33, 95% CI 1.19 to 4.57), reporting of multiple irAEs (ROR 3.96, 95% CI 2.85 to 5.52), reporting of cutaneous irAEs (ROR 1.83, 95% CI 1.24 to 2.71), and melanoma (ROR 1.47, 95% CI 1.04 to 2.06).</p><p><strong>Conclusions: </strong>This global pharmacovigilance study provides the largest case series of late-onset irAEs with ICIs to date and identifies characteristics of ICSRs associated with disproportionate reporting. Dedicated prospective observational studies focused on long-term sequelae, quality of life and survival of patients developing late-onset irAEs with ICIs should be planned to confirm whether these reporting characteristics are predictors of actual occurrence. Furthermore, translational research should be encouraged to clarify the molecular mechanisms underlying late-onset irAE development.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 11","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11535709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142566629","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":"Unlocking the therapeutic potential of the NKG2A-HLA-E immune checkpoint pathway in T cells and NK cells for cancer immunotherapy.","authors":"Yan Li, Zhu Li, Yisen Tang, Xiaomei Zhuang, Wanhua Feng, Patrick P C Boor, Sonja Buschow, Dave Sprengers, Guoying Zhou","doi":"10.1136/jitc-2024-009934","DOIUrl":"10.1136/jitc-2024-009934","url":null,"abstract":"<p><p>Immune checkpoint blockade, which enhances the reactivity of T cells to eliminate cancer cells, has emerged as a potent strategy in cancer therapy. Besides T cells, natural killer (NK) cells also play an indispensable role in tumor surveillance and destruction. NK Group 2 family of receptor A (NKG2A), an emerging co-inhibitory immune checkpoint expressed on both NK cells and T cells, mediates inhibitory signal via interaction with its ligand human leukocyte antigen-E (HLA-E), thereby attenuating the effector and cytotoxic functions of NK cells and T cells. Developing antibodies to block NKG2A, holds promise in restoring the antitumor cytotoxicity of NK cells and T cells. In this review, we delve into the expression and functional significance of NKG2A and HLA-E, elucidating how the NKG2A-HLA-E axis contributes to tumor immune escape via signal transduction mechanisms. Furthermore, we provide an overview of clinical trials investigating NKG2A blockade, either as monotherapy or in combination with other therapeutic antibodies, highlighting the responses of the immune system and the clinical benefits for patients. We pay special attention to additional immune co-signaling molecules that serve as potential targets on both NK cells and T cells, aiming to evoke more robust immune responses against cancer. This review offers an in-depth exploration of the NKG2A-HLA-E pathway as a pivotal checkpoint in the anti-tumor responses, paving the way for new immunotherapeutic strategies to improve cancer patient outcomes.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 10","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529472/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142564313","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":"Type I MET inhibitors cooperate with PD-1 blockade to promote rejection of hepatocellular carcinoma.","authors":"Ricardo DeAzevedo, Madeline Steiner, Broderick X Turner, Arthur Liu, Sherwin Newton, Joanna Schmidt, Rachel Fleming, Angelica Tolentino, Ahmed O Kaseb, Michael A Curran","doi":"10.1136/jitc-2024-009690","DOIUrl":"10.1136/jitc-2024-009690","url":null,"abstract":"<p><p>Blockade of the immune checkpoints programmed death-1 (PD-1) and cytotoxic lymphocyte antigen 4 has improved outcomes for patients with hepatocellular carcinoma (HCC), yet most still fail to achieve objective clinical benefit. MET plays key roles in both HCC tumorigenesis and immunosuppressive conditioning; however, inhibition of MET causes upregulation of PD-ligand 1 (PD-L1) suggesting the use of these inhibitors in the context of PD-1 blockade. We sought to investigate across the Hepa1-6, HCA-1 and diethylnitrosamine (DEN) models of HCC whether the combination of more specific type I versus more pleiotropic type II MET inhibitors would confer superior outcomes in combination with PD-1 blockade. While MET inhibition demonstrated cooperativity with αPD-1 across all three models, the type I MET inhibitor capmatinib showed optimal activity in combination and statistically significantly outperformed the combination with the type II inhibitor cabozantinib in the αPD-1 refractory DEN model. In both HCA-1 and DEN HCC, the capmatinib and αPD-1 combination enhanced CD8 T cell frequency and activation state while limiting intratumoral myeloid immune suppression. In vitro studies of antigen-specific T cell activation reveal significantly less inhibition of effector cytokine production and proliferation by capmatinib versus by type II or type III MET inhibitors. These findings suggest significant potential for clinical HCC combination studies of type I MET inhibitors and PD-1 blockade where prior trials using type II inhibitors have yielded limited benefit.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 10","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529525/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142545631","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":"Pancreatic cancer is feeling the heat.","authors":"Saumya Y Maru, Elizabeth M Jaffee","doi":"10.1136/jitc-2024-010124","DOIUrl":"10.1136/jitc-2024-010124","url":null,"abstract":"<p><p>Pancreatic adenocarcinoma (PDAC) is considered an immunologically 'cold' tumor that fails to attract or support effector T cells. Most PDACs are resistant to immune checkpoint blockade due to the complex signaling pathways that exist within its tumor microenvironment. Recent advances in genomic and proteomic technology advances are finally uncovering the complex inflammatory cellular and intercellular signals that require modulation and reprogramming. The goal is to 'turn up the heat' on PDACs with combination immunotherapies that incorporate T cell activating agents and immune modulatory agents, and successfully eradicate tumors. Here, we discuss progress and promising new research that is moving the field toward this goal.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 10","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521919","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":"Inhibitory Fcγ receptor deletion enhances CD8 T cell stemness increasing anti-PD-1 therapy responsiveness against glioblastoma.","authors":"Keun Bon Ku, Chae Won Kim, Yumin Kim, Byeong Hoon Kang, Jeongwoo La, In Kang, Won Hyung Park, Stephen Ahn, Sung Ki Lee, Heung Kyu Lee","doi":"10.1136/jitc-2024-009449","DOIUrl":"10.1136/jitc-2024-009449","url":null,"abstract":"<p><strong>Background: </strong>Certain cancers present challenges for treatment because they are resistant to immune checkpoint blockade (ICB), attributed to low tumor mutational burden and the absence of T cell-inflamed features. Among these, glioblastoma (GBM) is notoriously resistant to ICB. To overcome this resistance, the identification of T cells with heightened stemness marked by T-cell factor 1 (TCF1) expression has gained attention. Several studies have explored ways to preserve stem-like T cells and prevent terminal exhaustion. In this study, we investigate a target that triggers stem-like properties in CD8 T cells to enhance the response to ICB in a murine GBM model.</p><p><strong>Methods: </strong>Using <i>Fcgr2b^-/-</i> mice and a murine GL261 GBM model, we confirmed the efficacy of anti-programmed cell death protein-1 (PD-1) immunotherapy, observing improved survival. Analysis of immune cells using fluorescence-activated cell sorting and single-cell RNA sequencing delineated distinct subsets of tumor-infiltrating CD8 T cells in <i>Fcgr2b^-/-</i> mice. The crucial role of the stem-like feature in the response to anti-PD-1 treatment for reinvigorating CD8 T cells was analyzed. Adoptive transfer of OT-I cells into OVA-expressing GL261 models and CD8 T cell depletion in <i>Fcgr2b^-/-</i> mice confirmed the significance of <i>Fcgr2b^-/-</i> CD8 T cells in enhancing the antitumor response. Last, S1P₁ inhibitor treatment confirmed that the main source of tumor antigen-specific <i>Fcgr2b^-/-</i> CD8 T cells is the tumor-draining lymph nodes (TdLNs).</p><p><strong>Results: </strong>In a murine GBM model, anti-PD-1 monotherapy and single-Fc fragment of IgG receptor IIb (FcγRIIB) deletion exhibit limited efficacy. However, their combination substantially improves survival by enhancing cytotoxicity and proliferative capacity in tumor-infiltrating <i>Fcgr2b^-/-</i> CD8 T cells. The improved response to anti-PD-1 treatment is associated with the tumor-specific memory T cells (Ttsms) exhibiting high stemness characteristics within the tumor microenvironment (TME). Ttsms in the TdLN thrives in a protective environment, maintaining stem-like characteristics and serving as a secure source for tumor infiltration. This underscores the significance of FcγRIIB ablation in triggering Ttsms and enhancing ICB therapy against GBM.</p><p><strong>Conclusions: </strong>Deletion of FcγRIIB on CD8 T cells leads to the generation of a Ttsms, which is localized in TdLN and protected from the immunosuppressive TME. Incorporating these highly stemness-equipped Ttsms enhances the response to anti-PD-1 therapy in immune-suppressed brain tumors.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 10","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500810","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":"Ten challenges and opportunities in computational immuno-oncology.","authors":"Riyue Bao, Alan Hutson, Anant Madabhushi, Vanessa D Jonsson, Spencer R Rosario, Jill S Barnholtz-Sloan, Elana J Fertig, Himangi Marathe, Lyndsay Harris, Jennifer Altreuter, Qingrong Chen, James Dignam, Andrew J Gentles, Edgar Gonzalez-Kozlova, Sacha Gnjatic, Erika Kim, Mark Long, Martin Morgan, Eytan Ruppin, David Van Valen, Hong Zhang, Natalie Vokes, Daoud Meerzaman, Song Liu, Eliezer M Van Allen, Yi Xing","doi":"10.1136/jitc-2024-009721","DOIUrl":"10.1136/jitc-2024-009721","url":null,"abstract":"<p><p>Immuno-oncology has transformed the treatment of cancer, with several immunotherapies becoming the standard treatment across histologies. Despite these advancements, the majority of patients do not experience durable clinical benefits, highlighting the imperative for ongoing advancement in immuno-oncology. Computational immuno-oncology emerges as a forefront discipline that draws on biomedical data science and intersects with oncology, immunology, and clinical research, with the overarching goal to accelerate the development of effective and safe immuno-oncology treatments from the laboratory to the clinic. In this review, we outline 10 critical challenges and opportunities in computational immuno-oncology, emphasizing the importance of robust computational strategies and interdisciplinary collaborations amid the constantly evolving interplay between clinical needs and technological innovation.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 10","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11529678/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142500816","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}