Kupffer Cell Calibration of T Cell Responses via VSIG4-CD5 Interaction Promotes Tumor Evasion [bulkRNA]

Liver metastasis often resists T cell-based immunotherapy, indicating an adaptation of metastatic tumors towards reduced immunogenicity in the liver. Here we demonstrate that VSIG4, an immune checkpoint molecule predominantly expressed on Kupffer cells, plays an opposing role in determining the growth of liver metastases with varying antigenicity by modulating cognate TCR signaling through its interaction with CD5. Mechanistically, VSIG4-CD5 engagement impedes activation of low-affinity CD8+ T cells while enhancing responses of high-affinity CD8+ T cells by rescuing them from activation-induced cell death. This bi-directional regulation favors growth of metastatic tumor clones with low antigenicity, and fosters an T cell-unfavorable immune landscape as metastatic liver cancer progresses. Blockade of VSIG4-CD5 interaction with a newly generated anti-VSIG4 nanoantibody sensitizes liver metastases to anti-PDL1 therapy, achieving remarkably synergistic efficacy in mice. Our findings provide mechanistic insights into cancer immunoediting in liver metastasis and propose a promising approach for treating immunologically cold tumors.