GSDMD is associated with survival in human breast cancer but does not impact anti-tumor immunity in a mouse breast cancer model

Article Article scientifique Article GSDMD is associated with survival in human breast cancer but does not impact anti-tumor immunity in a mouse breast cancer model eng 2024-08-19 2024-08-19 author Boersma Bart Nicolaas 928705 author Puddinu Viola 868008 author Huard Arnaud 967409 Département de médecine (DEMED) author Fauteux-Daniel Sébastien 956306 author Wirapati Pratyaksha 982767 author Guedri Sofia 921534 author Tille Jean-Christophe 87627 author Mckee Thomas Alexander 549937 Département de pathologie et immunologie (PATIM) author Pittet Mikaël 0000-0002-2060-4691 917678 Département de pathologie et immunologie (PATIM) author Palmer-Lourenco Gaby 0000-0001-7567-1798 45743 Département de médecine (DEMED) author Bourquin Carole 0000-0003-3862-4583 854541 Section des sciences pharmaceutiques (FARMA) 1396777 10.3389/fimmu.2024.1396777 39224600 1664-3224 PMC11366651 https://www.frontiersin.org/articles/10.3389/fimmu.2024.1396777/full <p> Inflammation plays a pivotal role in cancer development, with chronic inflammation promoting tumor progression and treatment resistance, whereas acute inflammatory responses contribute to protective anti-tumor immunity. Gasdermin D (GSDMD) mediates the release of pro-inflammatory cytokines such as IL-1β. While the release of IL-1β is directly linked to the progression of several types of cancers, the role of GSDMD in cancer is less clear. In this study, we show that GSDMD expression is upregulated in human breast, kidney, liver, and prostate cancer. Higher GSDMD expression correlated with increased survival in primary breast invasive carcinoma (BRCA), but not in liver hepatocellular carcinoma (LIHC). In BRCA, but not in LIHC, high GSDMD expression correlated with a myeloid cell signature associated with improved prognosis. To further investigate the role of GSDMD in anticancer immunity, we induced breast cancer and hepatoma tumors in GSDMD-deficient mice. Contrary to our expectations, GSDMD deficiency had no effect on tumor growth, immune cell infiltration, or cytokine expression in the tumor microenvironment, except for Cxcl10 upregulation in hepatoma tumors. In vitro and in vivo innate immune activation with TLR ligands, that prime inflammatory responses, revealed no significant difference between GSDMD-deficient and wild-type mice. These results suggest that the impact of GSDMD on anticancer immunity is dependent on the tumor type. They underscore the complex role of inflammatory pathways in cancer, emphasizing the need for further exploration into the multifaceted effects of GSDMD in various tumor microenvironments. As several pharmacological modulators of GSDMD are available, this may lead to novel strategies for combination therapy in cancer. </p> Toll-like receptor 7 Breast cancer Cancer immunology Gasdermin D Immunotherapy Dewey 615 Dewey 616.07 Dewey 617 Swiss National Science Foundation HMGB1 and Gasdermin D: intratumoral targets to improve the response to cancer immunotherapy 182317 CH Projects Swiss National Science Foundation Biology and function of interleukin-38 in keratinocytes 188470 CH Projects Swiss National Science Foundation Regulation and function of interleukin-38 in oxidative stress 219251 CH Projects Swiss National Science Foundation Gasotransmitters in triple negative breast cancer (full proposal) 198887 CH Programmes 137 Département de pathologie et immunologie 21F 31 Section des sciences pharmaceutiques 17 63 Département d'anesthésiologie, pharmacologie, soins intensifs et urgences 229 false 1326 Biologie des cytokines de la famille de l'interleukine-1 1022 1278 Immunopharmacologie du cancer 1336 Comprendre et manipuler le système immunitaire pour lutter contre le cancer 1024 476 Lymphomes MALT et réplication virale 807 https://doi.org/10/gt7cs2 Frontiers in immunology 15 117cb672-24e9-4ec7-8c1e-749be4ab3b9c Article (Published version) Public fimmu-15-1396777.pdf 3214043 application/pdf CC BY-4.0 70cd4e28af3e38d4d30ff5083d7cf1992f73b9634a37af239c64ea1543cc3d0a fce3071b-5925-48af-bea8-2a07123df500 Supplemental data Public 7407619.zip 4521013 application/zip 3022913299e3bb23263d893bf60685e5daeb4bc12a9c63e242a4570309b292ca openAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie Faculté des sciences / Section des sciences pharmaceutiques Faculté de médecine / Section de médecine clinique / Département d'anesthésiologie, pharmacologie, soins intensifs et urgences

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GSDMD is associated with survival in human breast cancer but does not impact anti-tumor immunity in a mouse breast cancer model	Frontiers in immunology			2024	197	72

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