Abstract 3992: Immune regulation of disseminated tumor cell clearance versus metastatic growth

Abstract

Abstract Metastatic disease is the end stage of extremely inefficient processes that entail overcoming multiple barriers including anti-tumor immunity. Although evidences from preclinical and clinical settings suggest that dissemination of malignant cells is an early process, majority of disseminated cells either eliminated or remain dormant in distant organs, while very few cells eventually develop successful metastasis. Therefore, it is widely accepted that dynamic and reversible tumor cell plasticity is required for metastasis, however, in vivo steps and molecular mechanisms are poorly elucidated. We provide evidence that monocytic and granulocytic subsets of myeloid derived suppressor cells (m-MDS, g-MDSC) infiltrated in primary 4T1 tumor and distant organs with different time kinetics regulate spatiotemporal tumor plasticity. Using co-culture experiments and syngeneic mouse models of murine 4T1 (metastatic) tumor, we demonstrated that tumor infiltrated m-MDSCs facilitate tumor cell dissemination from the primary site by inducing the EMT/CSC phenotype. In contrast, g-MDSCs infiltrated in the lungs support metastatic growth by reverting the EMT/CSC phenotype and thus promoting tumor cell proliferation. In contrast, less invasive EMT6 tumors fail to induce efficient pulmonary infiltration of g-MDSCs and results in clearance of disseminated tumor cells in the lungs. Gene expression analyses of tumors and MDCS subsets in primary tumor site and distant organs at different time points reveal mechanistic temporal regulation of in vivo tumor plasticity by m-MDSC and g-MDSC subsets in 4T1 tumor-bearing mice. However, the lung microenvironment of EMT6 tumor-bearing mice display a gene expression signature of anti-tumor immunity which predict better survival in breast cancer patients. In our functional studies, we demonstrate that EMT6 tumor-bearing animals efficiently eliminate disseminated tumor cells in the lungs. Furthermore, g-MDSCs isolated from 4T1-tumor bearing animals significantly enhance metastatic growth of already disseminated tumor cells. Consistent with the “seed and soil” hypothesis, our studies provide a molecular mechanism by which the immune system regulate spatiotemporal tumor plasticity and generation of permissive or anti-tumorigenic microenvironment in distant organs determining the fate of disseminated tumor cells. Citation Format: Hasan Korkaya, Eunmi Lee, Raziye Piranioglu, Maria Ouzounova, Abdeljabar El-Andaloussi, Iskander Asm, Ahmet K. Korkaya, Gang Zhou, Ali Arbab, Paulo Rodriguez. Immune regulation of disseminated tumor cell clearance versus metastatic growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3992. doi:10.1158/1538-7445.AM2017-3992