LAMTOR1 degrades MHC-II via the endocytic in hepatocellular carcinoma

Abstract

Tumor cell surface antigen recognition is a major hallmark of cancer therapy, and loss of major histocompatibility complex class I (MHC-I) is the most common mechanism that impairs tumor cell surface antigen processing and expression. In addition to this, MHC-II regulates antigen presentation in CD4+ T cell immune responses involved in tumor killing by CD8+ T cells, whereas the regulation of endocytosis regulating MHC-II antigen presentation has not been reported. Therefore, the regulation of the endocytosis pathway on the expression of MHC-II surface level and anti-tumor T cell response remains to be explored. In this experiments, we found that LAMTOR1 regulates the endocytic pathway through the GTPase domain of DNM2 and triggers the formation of autophagosomes. We performed flow cytometry and western blotting analyses, which revealed that the expression of MHC-II molecules on the surface of cells is influenced by LAMTOR1 through the endocytic pathway. We showed that the expression of MHC-II molecules, which recognize CD4 + T cells on the surface of cells, was regulated by LAMTOR1 through an endocytic pathway. By co-culture experiments, we showed that CD8 +/CD4 + T cells exhibit substantially higher levels of tumor cell apoptosis than those observed when HCC cells were co-cultured with CD8 + T cells alone. This study revealed that LAMTOR1 decreases the expression levels of MHC-II on cell surfaces in order to reduce antigen expression, leading to a decrease in anti-tumor T cell responses.

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“…Recently, the importance of MHCII cell surface expression levels in cancer therapy has been recognized. The reduced expression of the cell surface antigen presentation protein MHCII in hepatocellular carcinoma has been shown to promote progression of cancer [ 43 ]. Additionally, the MHCII expression level determines the effectiveness of anti-PD-1/PD-L1 immune checkpoint therapy [ 44 , 45 ].…”

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“…Recently, the importance of MHCII cell surface expression levels in cancer therapy has been recognized. The reduced expression of the cell surface antigen presentation protein MHCII in hepatocellular carcinoma has been shown to promote progression of cancer 42 . Additionally, the MHCII expression level determines the effectiveness of anti-PD-1/PD-L1 immune checkpoint therapy 43,44 .…”