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

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.