Kupffer cell calibration of T cell responses via VSIG4-CD5 interaction promotes tumor evasion.

Liver metastases can resist T cell immunotherapies, indicating an adaptation of metastatic tumors toward reduced immunogenicity in the liver. Here we show that VSIG4, an immune checkpoint molecule predominantly expressed by Kupffer cells, has an opposing function in determining the growth of liver metastases with distinct antigenicity by modulating cognate T cell antigen receptor signaling through an interaction with CD5. 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 bidirectional regulation favors the outgrowth of poorly immunogenic metastatic tumor clones and fosters an immune landscape that is unfavorable to T cells as metastatic liver cancer progresses. We also show that blockade of VSIG4-CD5 interaction using a nanoantibody to VSIG4 sensitizes liver metastases to anti-PD-L1 therapy, achieving synergistic efficacy in mice. These findings provide mechanistic insights into cancer immunoediting during liver metastasis and a possible approach for treating immunologically cold tumors.