Journal for Immunotherapy of Cancer最新文献

{"title":"Neoantigen architectures define immunogenicity and drive immune evasion of tumors with heterogenous neoantigen expression.","authors":"Malte Roerden, Andrea B Castro, Yufei Cui, Noora Harake, Byungji Kim, Jonathan Dye, Laura Maiorino, Forest M White, Darrell J Irvine, Kevin Litchfield, Stefani Spranger","doi":"10.1136/jitc-2024-010249","DOIUrl":"10.1136/jitc-2024-010249","url":null,"abstract":"<p><strong>Background: </strong>Intratumoral heterogeneity (ITH) and subclonal antigen expression blunt antitumor immunity and are associated with poor responses to immune-checkpoint blockade immunotherapy (ICB) in patients with cancer. The underlying mechanisms however thus far remained elusive, preventing the design of novel treatment approaches for patients with high ITH tumors.</p><p><strong>Methods: </strong>We developed a mouse model of lung adenocarcinoma with defined expression of different neoantigens (NeoAg), enabling us to analyze how these impact antitumor T-cell immunity and to study underlying mechanisms. Data from a large cancer patient cohort was used to study whether NeoAg architecture characteristics found to define tumor immunogenicity in our mouse models are linked to ICB responses in patients with cancer.</p><p><strong>Results: </strong>We demonstrate that concurrent expression and clonality define NeoAg architectures which determine the immunogenicity of individual NeoAg and drive immune evasion of tumors with heterogenous NeoAg expression. Mechanistically, we identified concerted interplays between concurrent T-cell responses induced by cross-presenting dendritic cells (cDC1) mirroring the tumor NeoAg architecture during T-cell priming in the lymph node. Depending on the characteristics and clonality of respective NeoAg, this interplay mutually benefited concurrent T-cell responses or led to competition between T-cell responses to different NeoAg. In tumors with heterogenous NeoAg expression, NeoAg architecture-induced suppression of T-cell responses against branches of the tumor drove immune evasion and caused resistance to ICB. Therapeutic RNA-based vaccination targeting immune-suppressed T-cell responses synergized with ICB to enable control of tumors with subclonal NeoAg expression. A pan-cancer clinical data analysis indicated that competition and synergy between T-cell responses define responsiveness to ICB in patients with cancer.</p><p><strong>Conclusions: </strong>NeoAg architectures modulate the immunogenicity of NeoAg and tumors by dictating the interplay between concurrent T-cell responses mediated by cDC1. Impaired induction of T-cell responses supports immune evasion in tumors with heterogenous NeoAg expression but is amenable to NeoAg architecture-informed vaccination, which in combination with ICB portrays a promising treatment approach for patients with tumors exhibiting high ITH.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 11","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552027/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142619415","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":"Bendamustine-rituximab elicits dual tumoricidal and immunomodulatory responses via cGAS-STING activation in diffuse large B-cell lymphoma.","authors":"Ruipei Xiao, Wenli Zhao, Wei Lin, Yudian Xiao, Jie Ren, Yang Zhou, Wei Meng, Enguang Bi, Ling Jiang","doi":"10.1136/jitc-2024-009212","DOIUrl":"10.1136/jitc-2024-009212","url":null,"abstract":"<p><strong>Background: </strong>Bendamustine-rituximab (BR) therapy stands out as a promising alternative for elderly patients with diffuse large B-cell lymphoma (DLBCL), demonstrating notable efficacy when conventional regimens pose challenges. Despite its clinical success, the intricate mechanisms underlying BR therapy have remained elusive.</p><p><strong>Methods: </strong>DLBCL cell lines were used to investigate the mechanism of BR therapy in vitro. RNA-seq and Western blot were used to explore the target pathways of BR therapy. STING was knocked out using Crispr-cas9 and inhibited using H-151 to investigate its role in BR therapy. Bulk RNA-seq and single-cell RNA-seq data from patients were analyzed to investigate the association between STING and pyroptosis pathways, validated using STING downregulated cells. Flow cytometry, transwell experiments and co-culture experiments were performed to investigate the inflammatory phenotype of DLBCL cells after BR treatment and its effect on T-cell recruitment and activation.</p><p><strong>Results: </strong>This study elucidates that BR elicits direct tumoricidal effects by promoting apoptosis and inducing cell cycle arrest. The synergistic impact with rituximab is further potentiated by complement addition, demonstrating the pivotal role of in vivo antibody-dependent cellular cytotoxicity. Moreover, our investigation reveals that, through a cGAS-STING-dependent pathway, prolonged exposure to BR induces pyroptosis in DLBCL cells. Activation of the cGAS-STING pathway by BR therapy triggers the release of inflammatory factors and upregulates major histocompatibility complex molecules, shaping an immunologically hot tumor microenvironment.</p><p><strong>Conclusions: </strong>This unique dual influence not only directly targets DLBCL cells but also engages the patient's immune system, paving the way for innovative combination therapies. The study provides comprehensive insights into the multifaceted actions of BR in DLBCL, offering a foundation for refined and personalized treatment strategies in elderly patients.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 11","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11551994/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621147","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":"Depletion of conventional CD4⁺ T cells is required for robust priming and dissemination of tumor antigen-specific CD8⁺ T cells in the setting of anti-CD4 therapy.","authors":"Delaney E Ramirez, Christo P C Dragnev, Tyler G Searles, Nathaniel Spicer, Tiffany Chen, J Louise Lines, Aaron R Hawkes, Wilson L Davis, Asmaa Mohamed, Keisuke Shirai, Joseph D Phillips, Pamela C Rosato, Yina H Huang, Mary Jo Turk","doi":"10.1136/jitc-2024-010170","DOIUrl":"10.1136/jitc-2024-010170","url":null,"abstract":"<p><strong>Background: </strong>Overcoming immune suppression is a major barrier to eliciting potent CD8⁺ T cell responses against cancer. Treatment with anti-CD4 monoclonal antibody is an effective means for eliminating CD4⁺Foxp3⁺ regulatory (Treg) cells in preclinical models and has also demonstrated efficacy in early clinical trials. However, the underlying basis for treatment efficacy, more specifically the implications of codepleting other CD4-expressing cell compartments in tumor-bearing hosts, is not well understood.</p><p><strong>Methods: </strong>Tumor-bearing mice were treated with anti-CD4 versus other therapies that preserve helper T cell function, and the priming, tissue distribution, and maintenance of tumor antigen-specific CD8 T cells were assessed. Antibody blockade and transgenic mouse models were used to determine the mechanisms of CD8 T cell priming. Single-cell RNA-sequencing (scRNAseq) was used to further characterize CD8 T cells that are primed by anti-CD4 therapy and to identify immunosuppressive CD4 T cell subsets in human melanoma following immune checkpoint blockade (ICB).</p><p><strong>Results: </strong>Comparing anti-CD4 to dual ICB therapy, we show that anti-CD4 facilitates more robust priming of TCF-1⁺, IL-2-producing, tumor-specific CD8⁺ T cells that disseminate to tissues and form memory. By decoupling priming from homeostatic proliferation and associated cytokines, we find that anti-CD4 functions independently of creating homeostatic space for CD8⁺ T cells. We also show that depletion of CD4-expressing antigen-presenting cell subsets is not required for anti-CD4 efficacy. Instead, robust tumor-specific CD8⁺ T cell priming and memory generation required the removal of total antigen-specific CD4⁺ T cells, including both Tregs and CD4⁺ Foxp3-negative conventional (Tconv) cells. In particular, the elimination of CD4⁺ Tconv cells was necessary for the accumulation and maturation of conventional type-1 dendritic cells in tumor-draining LNs, which were required for CD8⁺ T cell priming. Accordingly, anti-CD4 treatment restored CD8⁺ T cell responses in mice cotreated with dual ICB. scRNAseq of melanoma tumors from patients who received ICB revealed the presence of Tr1 and Treg subsets, as well as CD4⁺ Tconv subsets that lacked clear transcriptional evidence of helper differentiation.</p><p><strong>Conclusions: </strong>These findings underscore the underappreciated benefit of depleting CD4⁺ Tconv cells to promote systemic primary and memory CD8⁺ T cell responses against cancer.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 11","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552015/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621157","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":"Correction: Inhibition of PNCK inflames tumor microenvironment and sensitizes head and neck squamous cell carcinoma to immune checkpoint inhibitors.","authors":"","doi":"10.1136/jitc-2024-009893corr1","DOIUrl":"https://doi.org/10.1136/jitc-2024-009893corr1","url":null,"abstract":"","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 11","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552004/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621150","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":"Magnitude of antigen-specific T-cell immunity the month after completing vaccination series predicts the development of long-term persistence of antitumor immune response.","authors":"John B Liao, James Y Dai, Jessica L Reichow, Jong-Baeck Lim, Katie M Hitchcock-Bernhardt, Sasha E Stanton, Lupe G Salazar, Theodore A Gooley, Mary L Disis","doi":"10.1136/jitc-2024-010251","DOIUrl":"10.1136/jitc-2024-010251","url":null,"abstract":"<p><strong>Background: </strong>For best efficacy, vaccines must provide long-lasting immunity. To measure longevity, memory from B and T cells are surrogate endpoints for vaccine efficacy. When antibodies are insufficient for protection, the immune response must rely on T cells. The magnitude and differentiation of effective, durable immune responses depend on antigen-specific precursor frequencies. However, development of vaccines that induce durable T-cell responses for cancer treatment has remained elusive.</p><p><strong>Methods: </strong>To address long-lasting immunity, patients with HER2+ (human epidermal growth factor receptor 2) advanced stage cancer received HER2/neu targeted vaccines. Interferon-gamma (IFN-γ) enzyme-linked immunosorbent spot measuring HER2/neu IFN-γ T cells were analyzed from 86 patients from three time points: baseline, 1 month after vaccine series, and long-term follow-up at 1 year, following one in vitro stimulation. The baseline and 1-month post-vaccine series responses were correlated with immunity at long-term follow-up by logistic regression. Immunity was modeled by non-linear functions using generalized additive models.</p><p><strong>Results: </strong>Antigen-specific T-cell responses at baseline were associated with a 0.33-log increase in response at long-term follow-up, 95% CI (0.11, 0.54), p=0.003. 63% of patients that had HER2/neu specific T cells at baseline continued to have responses at long-term follow-up. Increased HER2/neu specific T-cell response 1 month after the vaccine series was associated with a 0.47-log increase in T-cell response at long-term follow-up, 95% CI (0.27, 0.67), p=2e-5. 74% of patients that had an increased IFN-γ HER2 response 1 month after vaccines retained immunity long-term. As the 1-month post-vaccination series precursor frequency of HER2+IFN-γ T-cell responses increased, the probability of retaining these responses long-term increased (OR=1.49 for every one natural log increase of precursor frequency, p=0.0002), reaching an OR of 20 for a precursor frequency of 1:3,000 CONCLUSIONS: Patients not destined to achieve long-term immunity can be identified immediately after completing the vaccine series. Log-fold increases in antigen-specific precursor frequencies after vaccinations correlate with increased odds of retaining long-term HER2 immune responses. Further vaccine boosting or immune checkpoint inhibitors or other immune stimulator therapy should be explored in patients that do not develop antigen-specific T-cell responses to improve overall response rates.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 11","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552009/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621195","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":"Body mass index and type 2 diabetes mellitus as metabolic determinants of immune checkpoint inhibitors response in melanoma.","authors":"Yu Jen Alexander Jan, Cho-Han Chiang, Soravis Osataphan, Aleigha R Lawless, Kerry L Reynolds, Ryan J Sullivan","doi":"10.1136/jitc-2024-009769","DOIUrl":"10.1136/jitc-2024-009769","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) have improved survival outcomes in melanoma. Studies exploring the correlations between body mass index (BMI), type 2 diabetes (T2DM) and the outcomes of ICI treatment have yielded inconsistent results. In this study, we aim to investigate the effects of BMI and T2DM on survival outcomes of patients with melanoma receiving ICIs.</p><p><strong>Methods: </strong>A retrospective multicenter cohort of patients with melanoma treated with ICIs was analyzed. Overall survival was evaluated with Kaplan-Meier survival analysis, univariate Cox and multivariate Cox proportional hazards model. Propensity-score matching (1:1) analysis between overweight and non-overweight groups was done and survival analyses and Cox analyses were performed again. Subgroup analyses and secondary analyses stratifying patients with different weights and T2DM statuses were also performed.</p><p><strong>Results: </strong>A total of 2,078 patients were included, of whom 1,412 were overweight (BMI≥25 kg/m²) and 666 were non-overweight (BMI<25 kg/m²). Overweight patients had better overall survival compared with non-overweight (median 71.7 vs 36.7 months, p<0.001). Patients with T2DM had worse overall survival compared with patients without T2DM (median 28.5 vs 67.3 months, p<0.001). After propensity-score matching (666 overweight were matched to 666 non-overweight), overweight patients remained to have better overall survival compared with non-overweight (median 67.7 vs 36.7 months, p<0.001). Patients with T2DM had worse survival in univariate Cox (HR 1.71, (95% CI: 1.20 to 2.43)) and multivariate Cox (HR 1.58, (95% CI: 1.08 to 2.31)) analyses. Overweight patients without T2DM had the best survival outcomes compared with other weight and T2DM combinations.</p><p><strong>Conclusion: </strong>In patients with melanoma treated with ICIs, being overweight had better survival outcomes compared with non-overweight. Having T2DM was associated with worse survival compared with those without T2DM. Further studies are needed to investigate the underlying mechanisms of these associations.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 11","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604634","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":"TMED inhibition suppresses cell surface PD-1 expression and overcomes T cell dysfunction.","authors":"David W Vredevoogd, Georgi Apriamashvili, Pierre L Levy, Sanju Sinha, Zowi R Huinen, Nils L Visser, Beaunelle de Bruijn, Julia Boshuizen, Susan E van Hal-van Veen, Maarten A Ligtenberg, Onno B Bleijerveld, Chun-Pu Lin, Judit Díaz-Gómez, Santiago Duro Sánchez, Ettai Markovits, Juan Simon Nieto, Alex van Vliet, Oscar Krijgsman, Gal Markel, Michal J Besser, Maarten Altelaar, Eytan Ruppin, Daniel S Peeper","doi":"10.1136/jitc-2024-010145","DOIUrl":"10.1136/jitc-2024-010145","url":null,"abstract":"<p><strong>Background: </strong>Blockade of the programmed cell death protein 1 (PD-1) immune checkpoint (ICB) is revolutionizing cancer therapy, but little is known about the mechanisms governing its expression on CD8 T cells. Because PD-1 is induced during activation of T cells, we set out to uncover regulators whose inhibition suppresses PD-1 abundance without adversely impacting on T cell activation.</p><p><strong>Methods: </strong>To identify PD-1 regulators in an unbiased fashion, we performed a whole-genome, fluorescence-activated cell sorting (FACS)-based CRISPR-Cas9 screen in primary murine CD8 T cells. A dual-readout design using the activation marker CD137 allowed us to uncouple genes involved in PD-1 regulation from those governing general T cell activation.</p><p><strong>Results: </strong>We found that the inactivation of one of several members of the TMED/EMP24/GP25L/p24 family of transport proteins, most prominently TMED10, reduced PD-1 cell surface abundance, thereby augmenting T cell activity. Another client protein was cytotoxic T lymphocyte-associated protein 4 (CTLA-4), which was also suppressed by TMED inactivation. Treatment with TMED inhibitor AGN192403 led to lysosomal degradation of the TMED-PD-1 complex and reduced PD-1 abundance in tumor-infiltrating CD8 T cells (TIL) in mice, thus reversing T cell dysfunction. Clinically corroborating these findings, single-cell RNA analyses revealed a positive correlation between TMED expression in CD8 TIL, and both a T cell dysfunction signature and lack of ICB response. Similarly, patients receiving a TIL product with high TMED expression had a shorter overall survival.</p><p><strong>Conclusion: </strong>Our results uncover a novel mechanism of PD-1 regulation, and identify a pharmacologically tractable target whose inhibition suppresses PD-1 abundance and T cell dysfunction.</p>","PeriodicalId":14820,"journal":{"name":"Journal for Immunotherapy of Cancer","volume":"12 11","pages":""},"PeriodicalIF":10.3,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11552591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142604638","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":"WWOX tuning of oleic acid signaling orchestrates immunosuppressive macrophage polarization and sensitizes hepatocellular carcinoma to immunotherapy.","authors":"Shaoqing Liu, Shiguang Yang, Min Xu, Qiang Zhou, Jialei Weng, Zhiqiu Hu, Minghao Xu, Wenxin Xu, Yong Yi, Yi Shi, Qiongzhu Dong, Mien-Chie Hung, Ning Ren, Chenhao Zhou","doi":"10.1136/jitc-2024-010422","DOIUrl":"10.1136/jitc-2024-010422","url":null,"abstract":"<p><strong>Background: </strong>Immune checkpoint inhibitors (ICIs) are therapeutically effective for hepatocellular carcinoma (HCC) but are individually selective. This study examined the role of specific common fragile sites (CFSs) related gene in HCC immunotherapy.</p><p><strong>Methods: </strong>We analyzed HCC tissues using next-generation sequencing and flow cytometry via time-of-flight technology. A humanized orthotopic HCC mouse model, an in vitro co-culture system, untargeted metabolomics and a DNA pulldown assay were used to examine the function and mechanism of WWOX in the tumor immune response.</p><p><strong>Results: </strong>WWOX was the most upregulated CFS-related gene in HCC patients responsive to ICIs. WWOX deficiency renders HCC resistant to PD-1 treatment in humanized orthotopic HCC mouse model. Macrophage infiltration is increased and CD8 T-cell subset infiltration is decreased in WWOX-deficient HCC patients. HCC-derived oleic acid (OA) promotes macrophage conversion to an immunosuppressive phenotype. Mechanistically, WWOX deficiency promoted OA synthesis primarily via competitive binding of NME2 with KAT1, which promoted acetylation of NME2 at site 31 and inhibited NME2 binding to the SCD5 promoter region. Pharmacological blockade of SCD5 enhanced the antitumor effects of anti-PD-1 therapy.</p><p><strong>Conclusions: </strong>WWOX is a key factor for immune escape in HCC patients, which suggests its use as a biomarker for stratified treatment with ICIs in clinical HCC patients.</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/PMC11552608/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582972","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":"Role of <i>CD47</i> gene expression in colorectal cancer: a comprehensive molecular profiling study.","authors":"Hiroyuki Arai, Nishant Gandhi, Francesca Battaglin, Jingyuan Wang, Sandra Algaze, Priya Jayachandran, Shivani Soni, Wu Zhang, Yan Yang, Joshua Millstein, Jae Ho Lo, Davendra Sohal, Richard Goldberg, Michael J Hall, Aaron James Scott, Jimmy J Hwang, Emil Lou, Benjamin A Weinberg, John Marshall, Sanjay Goel, Joanne Xiu, W Michael Korn, Heinz-Josef Lenz","doi":"10.1136/jitc-2024-010326","DOIUrl":"https://doi.org/10.1136/jitc-2024-010326","url":null,"abstract":"<p><strong>Background: </strong>In patients with colorectal cancer (CRC), the therapeutic effects of conventional immune checkpoint inhibitors targeting the adaptive immune system are largely limited to those with microsatellite instability-high tumors. Meanwhile, new immunotherapies targeting the innate immune system are attracting increasing attention. CD47 is a representative innate immune checkpoint involved in the evasion of tumor cell phagocytosis by macrophages. This large-scale study comprehensively examined the molecular significance of <i>CD47</i> gene expression in CRC.</p><p><strong>Methods: </strong>We analyzed the next-generation sequencing data of DNA and RNA from 14,287 CRC cases included in the data set of a commercial Clinical Laboratory Improvement Amendments-certified laboratory (Caris Life Sciences). The cases were divided into two groups based on the median value of <i>CD47</i> gene expression levels. The molecular and immune profiles between the groups were compared, and the relationship between <i>CD47</i> expression and survival outcomes was further examined.</p><p><strong>Results: </strong>In <i>CD47</i>-high tumors, the proportion of consensus molecular subtypes 1 and 4 was significantly higher than in <i>CD47</i>-low tumors. The expression levels of damage-associated molecular pattern-related genes showed a positive correlation with <i>CD47</i> expression levels. Major oncogenic pathways, such as mitogen-activated protein kinase, phosphoinositide 3-kinase, angiogenesis, and transforming growth factor beta, were significantly activated in <i>CD47</i>-high tumors. Additionally, the expression levels of a panel of adaptive immune checkpoint genes and estimates of immune cells constituting the tumor microenvironment (TME) were significantly higher in <i>CD47</i>-high tumors.</p><p><strong>Conclusions: </strong><i>CD47</i> expression in CRC was associated with the activation of several oncogenic pathways and an immune-engaged TME. Our findings may provide valuable information for considering new therapeutic strategies targeting innate immune checkpoints in CRC.</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":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582929","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":"Intratumoral and peritumoral radiomics of MRIs predicts pathologic complete response to neoadjuvant chemoimmunotherapy in patients with head and neck squamous cell carcinoma.","authors":"Peiliang Lin, Wenqian Xie, Yong Li, Chenjia Zhang, Huiqian Wu, Huan Wan, Ming Gao, Faya Liang, Ping Han, Renhui Chen, Gui Cheng, Xuekui Liu, Song Fan, Xiaoming Huang","doi":"10.1136/jitc-2024-009616","DOIUrl":"10.1136/jitc-2024-009616","url":null,"abstract":"<p><strong>Background: </strong>For patients with locally advanced head and neck squamous cell carcinoma (HNSCC), combined programmed death receptor-1 inhibitor and chemotherapy improved response rate to neoadjuvant therapy. However, treatment response varies among patients. There is no tool to predict pathologic complete response (pCR) with high accuracy for now. To develop a tool based on radiomics features of MRI to predict pCR to neoadjuvant chemoimmunotherapy (NACI) may provide valuable assistance in treatment regimen determination for HNSCC.</p><p><strong>Methods: </strong>From January 2021 to April 2024, a total of 172 patients with HNSCC from three medical center, who received NACI followed by surgery, were included and allocated into a training set (n=84), an internal validation set (n=37) and an external validation set (n=51). Radiomics features were extracted from intratumoral and different peritumoral areas, and radiomics signature (Rad-score) for each area was constructed. A radiomics-clinical nomogram was developed based on Rad-scores and clinicopathological characteristics, tested in the validation sets, and compared with clinical nomogram and combined positive score (CPS) in predicting pCR.</p><p><strong>Results: </strong>The radiomics-clinical nomogram, incorporating peritumoral Rad-score, intratumoral Rad-score and CPS, achieved the highest accuracy with areas under the receiver operating characteristic curve of 0.904 (95% CI, 0.835 to 0.972) in the training cohort, 0.860 (95% CI, 0.722 to 0.998) in the internal validation cohort, and 0.849 (95% CI, 0.739 to 0.959) in the external validation cohort, respectively, which outperformed the clinical nomogram and CPS in predict pCR to NACI for HNSCC.</p><p><strong>Conclusion: </strong>A nomogram developed based on intratumoral and peritumoral MRI radiomics features outperformed CPS, a widely employed biomarker, in predict pCR to NACI for HNSCC, which would provide incremental value in treatment regimen determination.</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/PMC11552555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142582957","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}