[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-384109-105":3,"detail-sidebar-cat-0-en-105":79,"doc-detail-384109-en":129},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":72,"head_meta":74,"extra_data":76,"updated_unix":78},105,"en","mismatch-repair-deficiency-is-not-sufficient-to-elicit-tumor-immunogenicity","Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity","","Mismatch repair deficiency (MMRd) drives high tumor mutational burden (TMB) and is linked to sensitivity to immune checkpoint blockade (ICB), yet most MMRd tumors fail to durably respond. To clarify why, the study created autochthonous mouse models of MMRd lung and colon cancer and found no increased T cell infiltration or ICB response, driven by substantial intratumor mutation heterogeneity. Immunosurveillance reshaped clonal architecture without changing overall neoantigen burden, and T cells targeting subclonal neoantigens were blunted. In clinical trials of MMRd gastric and colorectal cancer, clonal neoantigen burden predicted ICB response, while subclonal burden did not.",{"@graph":14,"@context":71},[15,34,54],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & Report",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/mismatch-repair-deficiency-is-not-sufficient-to-elicit-tumor-immunogenicity/384109/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":48,"encodingFormat":47,"isAccessibleForFree":49,"interactionStatistic":50},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/mismatch-repair-deficiency-is-not-sufficient-to-elicit-tumor-immunogenicity/384109.png","ImageObject",300,407,{"name":42,"@type":43},"Stanford","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-09-24",true,{"@type":51,"interactionType":52,"userInteractionCount":22},"InteractionCounter",{"@type":53},"ViewAction",{"@type":55,"mainEntity":56},"FAQPage",[57,63,67],{"name":58,"@type":59,"acceptedAnswer":60},"Why do many MMRd tumors not respond durably to immune checkpoint blockade?","Question",{"text":61,"@type":62},"Despite association with high TMB, many MMRd tumors do not durably respond. The study attributes poor responses to substantial intratumor heterogeneity and blunted T-cell activity against subclonal neoantigens.","Answer",{"name":64,"@type":59,"acceptedAnswer":65},"What did the mouse models show about T cell infiltration and ICB response in MMRd cancer?",{"text":66,"@type":62},"The autochthonous MMRd lung and colon models did not show increased T cell infiltration or improved ICB response.",{"name":68,"@type":59,"acceptedAnswer":69},"Which neoantigen measure predicted ICB response in clinical trials of MMRd gastric and colorectal cancer?",{"text":70,"@type":62},"Clonal neoantigen burden predicted ICB response, whereas subclonal neoantigen burden did not.","https://schema.org",{"og:url":32,"og:type":73,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":75,"canonical":32},"index,follow",{"doc_id":77,"site_id":7},384109,1790293551,{"code":4,"msg":80,"data":81},"success",[82,86,90,94,99,104,109,113,118,121,125],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":83,"show_sort_weight":84,"slug":85},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":87,"show_sort_weight":88,"slug":89},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":91,"show_sort_weight":92,"slug":93},"Exam",70,"exam",{"id":95,"doc_module":4,"doc_module_name":25,"category_name":96,"show_sort_weight":97,"slug":98},5,"Comic",60,"comic",{"id":100,"doc_module":4,"doc_module_name":25,"category_name":101,"show_sort_weight":102,"slug":103},6,"Technology",50,"technology",{"id":105,"doc_module":4,"doc_module_name":25,"category_name":106,"show_sort_weight":107,"slug":108},7,"Healthcare",40,"healthcare",{"id":110,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":111,"slug":112},8,30,"research-report",{"id":114,"doc_module":4,"doc_module_name":25,"category_name":115,"show_sort_weight":116,"slug":117},9,"Religion & Spirituality",20,"religion-spirituality",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":119,"show_sort_weight":116,"slug":120},"World Cup","world-cup",{"id":122,"doc_module":4,"doc_module_name":25,"category_name":123,"show_sort_weight":122,"slug":124},10,"Lifestyle","lifestyle",{"id":126,"doc_module":4,"doc_module_name":25,"category_name":127,"show_sort_weight":95,"slug":128},19,"General","general",{"code":4,"msg":80,"data":130},{"doc_id":77,"user_id":131,"nickname":42,"user_avatar":132,"doc_module":4,"category_id":110,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":133,"file_id":134,"file_url":135,"file_type":136,"file_size":137,"view_count":22,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":111,"language":138,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":139,"faqs":140,"seo_title":141,"seo_description":12,"update_tm":142,"read_time":143},2336477552062,"https://ap-avatar.wpscdn.com/davatar_994ba38a5ba835b3df7d355c54d3ed8d","nature genetics  \nArticle [https://doi.org/10.1038/s41588-023-01499-4](https://doi.org/10.1038/s41588-023-01499-4)  \nMismatch repair deficiency isnot sufficient toelicit tumor immunogenicity  \nReceived: 9 March 2023  \nAccepted: 7 August 2023  \n\n| Published online: 14 September 2023 |\n| --- |\n|  Check for updates |\n\nPeter M. K. Westcott  1,5 , Francesc Muyas2, Haley Hauck1,6,  \nOlivia C. Smith  1,6, Nathan J. Sacks1, ZackeryA. Ely1,3, Alex M. Jaeger1, William M. Rideout III1, Daniel Zhang  1, Arjun Bhutkar1, Mary C. Beytagh  1, DavidA. Canner1, Grissel C. Jaramillo1, Roderick T. Bronson4, Santiago Naranjo1, Abbey Jin1, J. J. Patten  1, Amanda M. Cruz1, Sean-Luc Shanahan1,  \nIsidro Cortes-Ciriano  2  & Tyler Jacks  1,4   \nDNA mismatch repair deficiency (MMRd) is associated with a high tumor mutational burden (TMB) and sensitivity to immune checkpoint blockade (ICB) therapy. Nevertheless, most MMRd tumors do not durably respond to ICBand critical questions remain about immunosurveillance and TMBin these tumors. In the present study, we developed autochthonous mouse models of MMRd lung and colon cancer. Surprisingly, these models did not display increased T cell infiltration or ICB response, which we showed tobe the result of substantial intratumor heterogeneity of mutations. Furthermore, we found that immunosurveillance shapes the clonal architecture but not the overall burden of neoantigens, and T cell responses against subclonal neoantigens are blunted. Finally, we showed that clonal, but not subclonal, neoantigen burden predictsICB response in clinical trials of MMRd gastric and colorectal cancer. These results provide important context for understanding immune evasion in cancers with a high TMBand have major implications for therapies aimed at increasing TMB.  \nImmunotherapy has revolutionized the treatment landscape of many cancers, particularly those with a high tumor mutational burden (TMB)1–5. Somatic mutations can generate neoantigens capable of eliciting tumor-specific T cell responses6,7, and it is widely believed that increased TMB renders tumors susceptible to immune attack after ICB treatment. Indeed, multiple pan-cancer meta-analyses have shown that TMB is oneof the strongest predictors ofICB response8–10, leading to approval by the US Food and Drug Administration (FDA) of pembrolizumab (anti-PD-1) for all tumors based on high TMB alone. In particular, MMRdisassociated with some of the highest TMBs observed in cancer (hypermutation)11–15and remarkable response ratestopembrolizumab2,5. However, more than half the patients with MMRd tumors do not durably respond and TMB does not stratify responders2,5. This  \nunderscores a critical need to understand what factors beyond TMB mediate efficacy. There are also conflicting studies suggesting that TMB is an imperfect biomarker of immunotherapy response16 and argue that FDA approval of pembrolizumab based onTMB alone maybe too broad17. Specifically, TMB provides limited to no additional predictive value within specific subsets of cancer known to have high rates of response to ICB, like those with MMRd2,5.  \nOne factor that may dilute the power of TMB asa biomarker ofICB response is intratumor heterogeneity (ITH) of mutations or, simply defined, the fraction of mutations that are subclonal—present in a minority of tumor cells. Subclonal neoantigens could be deleted with minimal impact on tumor fitness18 or fail to elicit productive T cell responses19. Indeed, it has been observed inhuman cancer that ITHis  \n1David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA. 2European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton, Cambridge, UK. 3Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA. 4Rodent Histopathology Core, Harvard Medical School, Boston, MA, USA. 5Present address: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY,  \nUSA. 6These authors contributed ","cbCaibYwzr4FioXn","https://ap.wps.com/l/cbCaibYwzr4FioXn","pdf",19190074,"English","# Overview\n## Rationale: TMB and ICB in MMRd tumors\n## Study approach and key findings\n# Immunotherapy background and biomarker limits\n## TMB as an imperfect predictor\n## Intratumor heterogeneity and neoantigen clonality\n# Experimental modeling\n## Autochthonous mouse model construction\n## Preclinical ICB sensitivity testing","[{\"question\":\"Why do many MMRd tumors not respond durably to immune checkpoint blockade?\",\"answer\":\"Despite association with high TMB, many MMRd tumors do not durably respond. The study attributes poor responses to substantial intratumor heterogeneity and blunted T-cell activity against subclonal neoantigens.\"},{\"question\":\"What did the mouse models show about T cell infiltration and ICB response in MMRd cancer?\",\"answer\":\"The autochthonous MMRd lung and colon models did not show increased T cell infiltration or improved ICB response.\"},{\"question\":\"Which neoantigen measure predicted ICB response in clinical trials of MMRd gastric and colorectal cancer?\",\"answer\":\"Clonal neoantigen burden predicted ICB response, whereas subclonal neoantigen burden did not.\"}]","Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity | PDF",1790261262,76]