Loss of major histocompatibility complex class I (MHC-I) is frequently observed in cancer and is associated with the escape of cancers from CD8+ T cell-mediated killing. Therefore, it is important to understand the immunological consequences of MHC-I deficiency and to find new therapeutic solutions for this class of tumors. In a study published in Cancer Cell, Beck et al. show that a treatment based on tumor-targeting antibodies and mRNA-encoded IL-2 can overcome therapy resistance in cancers with MHC-I deficiency.

To study the immunobiology of MHC-I-deficient tumors, the authors used cancer cell lines with deletion of β2-microglobulin (encoded by B2m), a component shared by all MHC-I molecules; such deletion leads to the complete absence of MHC-I surface expression and lack of recognition by tumor-antigen-specific CD8+ T cells. Using established colorectal cancer cell lines as models of immunogenic, so-called ‘hot’ tumors, the authors found less infiltration and activation of immune cells, such as CD8+ T cells, natural killer cells and type 1 conventional dendritic cells, in the microenvironment of B2m-knockout tumors than in that of the parental tumors. Although in vitro proliferation of cancer cells was not affected by knockout of B2m, this observed immunological ‘desertification’ of the tumor microenvironment (TME) was associated with accelerated tumor progression, as well as with resistance to different therapies, not limited to immune-based approaches.