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Guerin, M. V.

Publications and source records attributed to Guerin, M. V..

2 recordsLinked to original sources

T cell engagers convert acute tumor killing into endogenous vaccination

T cell engagers (TCEs) redirect T cells to kill tumors by cross-linking CD3{varepsilon} to a tumor antigen, independently of T cell receptor specificity. Some patients achieve remissions that persist long after drug clearance, but whether TCEs can couple acute cytotoxicity to the generation of lasting adaptive immunity remains unknown. Here, using an immunocompetent mouse model for clinical-grade human TCEs, we show that TCE-mediated killing initiates an endogenous vaccination cascade. Intravital two-photon imaging reveals a perforin-dependent cytotoxic wave that peaks within 24 hours, then subsides despite massive T cell accumulation. Single-cell transcriptomics and adoptive transfers demonstrate that memory CD8 T cells, the principal effector reservoir in mouse and human, transit through a progenitor-like state before differentiating into cytotoxic effectors with recall competence. Crucially, tumor lysis fuels cross-priming of tumor-specific CD8 T cells by XCR1 type 1 conventional dendritic cells, a cDC1-dependent step essential for durable tumor control and protective memory upon rechallenge.

immunology↗

TGFβ blocks STING-induced IFNα/ β release and tumor rejection in spontaneous mammary tumors

Type I interferons (IFN) are being rediscovered as potent anti-tumoral agents. Activation of the STimulator of INterferon Genes (STING) by DMXAA can induce a strong production of IFN/{beta} and the rejection of transplanted primary tumors. In the present study, we addressed whether targeting STING with DMXAA also leads to the regression of spontaneous MMTV-PyMT mammary tumors. We show that these tumors are refractory to DMXAA-induced regression. This is due to a blockade in the phosphorylation of IRF3 and the ensuing IFN/{beta} production. Mechanistically, we identified TGF{beta} abundant in spontaneous tumors, as a key molecule limiting this IFN-induced-tumor regression by DMXAA. Finally, blocking TGF{beta} restores the production of IFN by activated MHCII+ tumor-associated macrophages, and enables tumor regression induced by STING activation. On the basis of these findings, we propose that type I IFN-dependent cancer therapies could be greatly improved by combinations including the blockade of TGF{beta}.

cancer biology↗