Biological Consequences of MHC-II Expression by Tumor Cells in Cancer

Abstract

Immunotherapy has emerged as a key pillar of cancer treatment. To build upon the recent successes of immunotherapy, intense research efforts are aimed at a molecular understanding of antitumor immune responses, identification of biomarkers of immunotherapy response and resistance, and novel strategies to circumvent resistance. These studies are revealing new insight into the intricacies of tumor cell recognition by the immune system, in large part through MHCs. Although tumor cells widely express MHC-I, a subset of tumors originating from a variety of tissues also express MHC-II, an antigen-presenting complex traditionally associated with professional antigen-presenting cells. MHC-II is critical for antigen presentation to CD4⁺ T lymphocytes, whose role in antitumor immunity is becoming increasingly appreciated. Accumulating evidence demonstrates that tumor-specific MHC-II associates with favorable outcomes in patients with cancer, including those treated with immunotherapies, and with tumor rejection in murine models. Herein, we will review current research regarding tumor-enriched MHC-II expression and regulation in a range of human tumors and murine models, and the possible therapeutic applications of tumor-specific MHC-II.

Figure 1:. Pathway of IFN-γ mediated upregulation of tsMHC-II.

A) IFN-γ binds to the IFN-γ receptor (IFNGR) leading to JAK1/2 phosphorylation. JAK1/2 phosphorylates STAT1 which translocates to the nucleus and cooperates with other transcription factors, like IRF-1 to activate promoter IV of CIITA. CIITA is then translated and returns to the nucleus (not shown) where it acts as a scaffold for RFX family members and drives transcription of MHC-II related genes such as HLA-DR, DP, DQ, invariant chain (Ii), and HLA-DM. MHC-II alpha and beta chains are assembled and complexed with Ii in the endoplasmic reticulum. MHC-II bound to Ii and associated with HLA-DM bud off in a vesicle. Ii targets this vesicle to the acidic endosomal compartment. In the acidic environment, Ii is degraded to CLIP. HLA-DM catalyzes the release of CLIP and binding of antigen. Stabilized peptide:MHC-II complexes translocate to the cell surface where MHC-II can present antigen to CD4 T cells. B) MHC-I is generally constitutively expressed. Cytosolic proteins are degraded by the proteasome into peptide antigens. These antigens are loaded into the ER by TAP1/TAP2 transporter proteins where they can be loaded onto the assembled MHC-I alpha chain and β2M complex. This complex is transported through the Golgi (not shown) to the cell surface where it can present peptide antigens to CD8+ T cells.

Figure 2:. Cancer types which have been shown to express MHC-II.

A diverse subset of human tumors has been shown to express MHC-II. Those tumor types, and the outcomes associated with tsMHC-II are shown here.

Figure 3:. Mechanisms of tsMHC-II-mediated immunostimulation.

Mechanisms by which tsMHC-II has been proposed to affect immunity. 1) Cancer cells expressing MHC-II may secrete exosomes which can be immunostimulatory. 2) tsMHC-II may directly interact with CD4+ T cells to affect polarization and activation. 3) Cancer cells may secrete antigens which can be endocytosed and presented by pAPCs.