Abstract 70: Mechanisms of tumor dormancy induction mediated by abrogation of myeloid tgfβ signaling

Abstract

Persistence in a dormant state of residual tumor cells can occur following extended periods of clinical remission which may last decades. The disseminated tumor cells in distant organ sites eventually gain context dependent metastasis advantage during tumor progression. The mechanisms for dormancy induction or reactivation remain unclear. We found that the abrogation of myeloid TGF-β signaling induced tumor dormancy in breast cancer metastasis models. When given extended time, the TGFβRIImyeKO mice eventually developed similar number of metastatic nodules to that of control mice. We further validated our finding using an inducible system where reintroduction of TβRII diminished the tumor dormancy induction. RNAseq of dormant vs proliferative tumor cells identify 504 differential expressed genes, including those involving cell cycle arrest, IFNg response, MTOR signaling as well as MYC targeted genes. Immune cell profiling showed differential immune composition in micro and macro-tumor microenvironment between WT and TβRIImyeKO lung tissues. Of great interest, abrogation of myeloid specific TGF-β signaling increased the number of CD103+DCs that displayed elevated TNFa production, which in turn increased IFNg+ production in T cells leading to improved innate and adaptive immunity. Importantly, depletion of CD103 DCs in tumor-bearing TβRIImyeKO mice diminished the dormancy phenotype, which was not observed for the pDC depletion in the WT control mice. These data demonstrate that abrogation of myeloid specific TGF-β signaling improved the immune microenvironment, which induced tumor dormancy. Our data provide mechanistic insight and resources to understand the tumor dormancy. Citation Format: Abdul Ahad, Feng Leng, Hiroshi Ichise, Justin Gray, Olga Aprelikova, Maura O’Neill, Ronald Holewinski, Vishal N. Kopardé4, Yasuhiro Moriwaki, Christine Hollander, Ronald Germain, Thorkell Andresson, Yang Li. Mechanisms of tumor dormancy induction mediated by abrogation of myeloid tgfβ signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 70.