Abstract SY23-01: Targeting the reciprocal interplay between inflammation, fibrosis, and pro-tumor immunity

Abstract

Abstract Tumors are characterized by increased levels of remodeled and crosslinked extracellular matrix (ECM) proteins that progressively stiffen the tissue stroma. Transformed cells exhibit a perturbed oncogene-stimulated and ECM-tuned mechanophenotype that further stimulates ECM remodeling and stiffening. We have been exploring how these aberrant cell and tissue level forces arise and by what means these forces contribute to malignancy and metastasis, and how they promote tumor recurrence and treatment resistance. We use two and three dimensional culture models with tuned ECM stiffness, as well as transgenic and syngeneic mouse models, human PDX models and human biospecimens, in which ECM crosslinking and stiffness and integrin mechanosignaling are manipulated and quantified. Our work has thus far revealed that the tumor ECM is progressively remodeled, and stiffened, primarily by stromal fibroblasts. We determined that infiltrating pro-tumorigenic myeloid cells secrete factors that stimulate stromal fibroblasts to remodel and crosslink the ECM and that this occurs quite early during tumor evolution. The stromal-fibroblast stiffened ECM thereafter disrupts tissue organization, promotes cell growth and survival and drives cell invasion. The stiffened tumor stroma additionally drives angiogenesis, and activates STAT3 to increase expression of cytokines and chemokines that further stimulate immune cell infiltration. The stiffened ECM thereafter reprograms the infiltrating myeloid cells by altering integrin adhesions and TGFβ SMAD signaling to induce an ECM synthetic metabolic phenotype in the myeloid cells. The metabolically reprogrammed myeloid cells ultimately compromise arginine tissue availability and increase tissue levels of ornithine that severely disrupt CD8 T cell tissue infiltration and perturb their anti-tumor function to accelerate tumor aggression and metastatic dissemination. I will discuss the dynamic and reciprocal interplay between tissue tension and innate and acquired immunity. I will then present data to show how ECM stiffness is able to promote tumor aggression and metastasis by dysregulating anti-tumor immunity. I will end with a short discussion regarding approaches to design therapies informed by these results to improve cancer treatment. Citation Format: Valerie M. Weaver. Targeting the reciprocal interplay between inflammation, fibrosis, and pro-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY23-01.