CXCL10 mediates CD8+ T cells to facilitate vessel normalization and improve the efficacy of cetuximab combined with PD-1 checkpoint inhibitors in colorectal cancer

Abstract

The immunotherapy and anti-EGFR targeted treatment occupying a pivotal position in colorectal cancer (CRC), is still limited to a group of patients who display specific molecular alterations and inevitably escape from resistance, further studies are still needed in colorectal cancer. We found that chemokine ligand 10 (CXCL10) expression correlates with intratumoral CD8⁺ T cell infiltration and reprograms tumor vasculatures in colorectal cancer. CXCL10 overexpression not only suppressed tumor growth but also increased CD8⁺ T cell infiltration and induced tumor vascular normalization in vivo. Additionally, the growth inhibition and tumor vascular normalization induced by CXCL10 can be reversed by the depletion of CD8⁺ T cells in vivo. Mechanically, CXCL10 interacts with VCAN to mediate tumor vascular normalization. The VCAN expression correlated inversely with the expression of CXCL10 and the infiltration of CD8⁺ T cells in CRC. Elevated CXCL10 expression sensitized colorectal cancer cells to cetuximab/anti-PD1 combination therapy compared with cetuximab or anti-PD1 alone. We propose that CXCL10 could be used to increase the anti-EGFR therapy and immunotherapy effect, targeting both tumor vessels and immune cells in colorectal cancer.

Keywords: Anti-EGFR; CXCL10; Immunotherapy; VCAN; Vascular normalization.