Fibroblasts drive an immunosuppressive and growth-promoting microenvironment in breast cancer via secretion of Chitinase 3-like 1

Abstract

Cancer-Associated Fibroblasts (CAFs) are the most prominent stromal cell type in breast tumors. CAFs promote tumor growth and metastasis by multiple mechanisms, including by mediating tumor-promoting inflammation. Immune modulation in the tumor microenvironment plays a central role in determining disease outcome. However, the functional interactions of CAFs with immune cells are largely unknown. Here we report a novel signaling axis between fibroblasts, cancer cells and immune cells in breast tumors that drives an immunosuppressive microenvironment, mediated by CAF-derived Chi3L1. We demonstrate that Chi3L1 is highly upregulated in CAFs isolated from mammary tumors and pulmonary metastases of transgenic mice, and in the stroma of human breast carcinomas. Genetic ablation of Chi3L1 in fibroblasts in vivo attenuated tumor growth, macrophage recruitment and reprogramming to an M2-like phenotype, enhanced tumor infiltration by CD8+ and CD4+ T cells and promoted a Th1 phenotype. These results indicate that CAF-derived Chi3L1 promotes tumor growth and shifts the balance of the immune milieu towards type 2 immunity. Taken together, our findings implicate fibroblast-derived Chi3L1 as a novel key player in the complex reciprocal interactions of stromal cells that facilitate tumor progression and metastasis, and suggest that targeting Chi3L1 may be clinically beneficial in breast cancer.

Melanoma‐derived extracellular vesicles instigate proinflammatory signaling in the metastatic microenvironment

“…We previously demonstrated in mouse models of mammary carcinogenesis that paracrine signaling by breast cancer cells activates mammary and lung fibroblasts to become proinflammatory CAFs . In order to assess whether tumor‐derived reprogramming of fibroblasts also plays a role in melanoma metastasis, we incubated primary lung fibroblasts with melanoma conditioned medium (CM) and analyzed their activation by assessing CAF‐like characteristics.…”

“…We previously demonstrated in mouse models of mammary carcinogenesis that paracrine signaling by breast cancer cells activates mammary and lung fibroblasts to become proinflammatory CAFs. 14,25 In order to assess whether tumor-derived reprogramming of fibroblasts also plays a role in melanoma metastasis, we incubated primary lung fibroblasts with melanoma conditioned medium (CM) and analyzed their activation by assessing CAF-like characteristics. Since we observed in melanoma lung metastases in vivo enhanced collagen deposition and enhanced expression of αSMA, a marker of myofibroblasts, we initially analyzed the effect of tumor-secreted factors on fibroblast-mediated collagen contraction, typical of myofibroblasts.…”

The influence of microenvironment on tumor immunotherapy

“…Glycoprotein chitinase‐3‐like‐1 (Chi3L1) is highly expressed in CAFs and involved in fibrotic disorders. Depletion of Chi3L1 in CAFs promoted tumor growth and increased the infiltration of CD4 + T cells and CD8 + T cells in tumors .…”

Nanomaterials for cancer immunotherapy

“…Similarly, TAFs secrete factors like TGF-β and IDO to expand the Treg population [248]. TAFs also produce fibrin, increasing tumor fibrosis, which acts as physical barrier to T-cell infiltration [249, 250]. Furthermore, TAFs may inhibit T cell activity through PD-L1 or PD-L2 expression [251, 252].…”