Tumor cell-derived extracellular vesicles foster the immunosuppressive landscape of pancreatic cancer

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Abstract

Pancreatic cancer remains a devastating disease with limited therapeutic options. Accumulating evidence has shown that cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs), the predominant cells in the pancreatic cancer (PDAC) tumor microenvironment (TME), hinder anti-tumor immunity. However, the role of extracellular vesicles (EVs) in such process is poorly understood. In this study, using human bone-marrow-derived monocytes and PDAC tumor cells, we show that tumor cell-derived EVs (TC-EVs) induced monocyte differentiation towards M2-like immunosuppressive CD200R+/PD-L1+/HLA-DR- macrophages that express ALOX15b, that we identify as an independent PDAC poor-prognosis biomarker using a human pancreatic cancer metacohort. We also demonstrate that TC-EVs reprogram human primary PDAC CAFs, causing a fibronectin network reorganization associated with changes in extracellular matrix (ECM) composition, including alterations of the Wnt pathway elements such as SFRP1 enrichment. We further reveal that monocytes cultured on rSFRP1-enriched ECM differentiate also into M2-like immunosuppressive macrophages. Lastly, we demonstrate that both directly and indirectly TC-EVs, or rSFRP1-enriched ECM, driven differentiated macrophages hindered T-cell activation and subsequent anti-tumor activity. Our findings highlight novel, dual mechanisms of TC-EVs-mediated crosstalk, involving Alox15b+-Macrophages and SFRP1+-CAFs, that simultaneously contribute to foster the immunosuppressive ecosystem of pancreatic cancer.

Authors

Zainab Hussain, Claudio Montenegro, Christopher Rovera, Djamila Belghoula, Sarah simha Tubiana, Pascal Finetti, Eugenie Lohmann, Magda Rodrigues, Thomas Bertran, Ghislain Bidaut, Daniel Isnardon, Sophie Vasseur, Francois Bertucci, Stephane Audebert, Luc Camoin, Moacyr Rego, Richard Tomasini