Dual inhibition of TGFβ signaling and CSF1/CSF1R reprograms tumor-infiltrating macrophages and improves response to chemotherapy via suppressing PD-L1

Abstract

TGFβ contributes to chemoresistance in advanced colorectal cancer (CRC) via diverse immune-microenvironment mechanisms. Here, we found that cancer cell autonomous TGFβ directly triggered tumor programmed cell death 1 ligand 1 (PD-L1) upregulation, resulting in resistance to chemotherapy. Inhibition of tumor PD-L1 expression sensitized cancer cells to chemotherapy, reduced lung metastasis and increased the influx of CD8⁺ T cells. However, chemorefractory cancer cell-derived CSF1 recruited TAMs for TGFβ-mediated PD-L1 upregulation via a vicious cycle. High infiltration of macrophages was clinically correlated with the status of tumor PD-L1 after chemotherapy treatment in CRC patients. We found that depletion of immunosuppressive CSF1R⁺ TAM infiltration and blockade of the TGFβ receptor resulted in an increased influx of cytotoxic CD8⁺ T and effector memory CD8⁺ cells, a reduction in regulatory T cells, and a synergistic inhibition of tumor growth when combined with chemotherapy. These findings show that CSF1R⁺ TAMs and TGFβ are the dominant components that regulate PD-L1 expression within the immunosuppressive tumor microenvironment, providing a therapeutic strategy for advanced CRC patients.

Keywords: CRC; CSF1R; PD-L1; TAMs; TGF.