CXCL16-driven CD4+ T cells orchestrate immunosurveillance against MHC-I-deficient tumors

MHC-I loss is a prevalent mechanism for immune evasion and resistance to immunotherapy. However, the mechanisms by which MHC-I loss shapes the tumor microenvironment (TME) and influences the interactions between MHC-I-deficient tumors and immune cells, ultimately affecting tumor growth, remain largely unknown. Here, we found that MHC-I/B2M loss increased tumor growth rates in the MC38, AKR and LLC1 tumor models, but surprisingly led to regression of Hepa1-6 tumors. The effect of MHC-I/B2M loss on tumor growth was associated with the changes in immune infiltrates. CD4+ T cell, NK cells and macrophages were required to suppress the growth of MHC-I-deficient Hepa1-6 tumors, with CD4+ T cells appearing essential for maintaining of the tumoricidal phenotype of monocytes/macrophages and for recruiting NK cells and monocytes/macrophages. Moreover, the differential infiltration of CD4+ T cells was attributed to the upregulation of CXCL16 expression in Hepa1-6 upon loss of MHC-I/B2M, and the downregulation of CXCL16 due to MHC-I deficiency in other tumor models. CXCL16 exhibited a potent antitumor effect on MHC-I-deficient tumors by recruiting CD4+ T cells. In summary, CXCL16-driven CD4+ T cells are central regulators of antitumor immunity against MHC-I-deficient tumors. Overall design: To investigate the mechanisms of MHC-I loss effecting tumor growth and tumor microenvironment, we established 4 MHC-I-deficient tumor cell lines (MC38, AKR, LLC1, and Hepa1-6) in which B2m has been knocked out by sgRNA. The non-targeting sgRNA was used for control. We then performed gene expression profiling analysis using data obtained from RNA-seq of 4 paired different cell lines.