Targeting the MHC Class II antigen presentation pathway in cancer immunotherapy

Abstract

The success of immunotherapy relies on the participation of all arms of the immune system and the role of CD4+ T lymphocytes in preventing tumor growth is now well established. Understanding how tumors evade immune responses holds the key to the development of cancer immunotherapies. In this review, we discuss how MHC Class II expression varies in cancer cells and how this influences antitumor immune responses. We also discuss the means that are currently available for harnessing the MHC Class II antigen presentation pathway for the development of efficient vaccines to activate the immune system against cancer.

Figure 1. Antigen presentation pathway by MHC Class II. The MHC II-related proteins are synthesized in the endoplasmic reticulum (ER). Three MHC Class II αβ heterodimers bind to a trimer of invariant chains, thus forming a nonameric complex. That complex is directed to the multivesicular bodies (MVBs) directly via the trans-Golgi network or from the cell surface. In the MVBs, proteases degrade the invariant chain until only a small fragment called CLIP remains in the peptide-binding groove. Degradative processes in the acidic compartment generate peptides from the material acquired through phagocytosis or autophagy. The non-classical MHC Class II HLA-DM and -DO dimerize in the ER and localize in MVBs. Free HLA-DM interacts with HLA-DR and mediate peptide exchange following the inward budding of the limiting membrane. The peptide-loaded MHC Class II can then egress to the cell surface where antigen presentation takes place.

Figure 2. Transcriptional regulation of MHC Class II genes. The binding of interferon γ (IFNγ) to its receptor at the cell surface leads to the transcriptional activation of the Class II transactivator (CIITA). This transcription factor binds to the promoters of the invariant chain and MHC Class II genes. BLIMP-1 can block the transcription at such promoters by directly inhibiting CIITA upregulation. The expression can of the invariant chain can also be modulated by NF-κB in response to various pro-inflammatory signals. On the other hand, the binding of interleukin-10 (IL-10) to its receptor at the cell surface triggers the upregulation of MARCH1.

Figure 3. Post-translational regulation of MHC Class II trafficking. From the cell surface, the mature peptide-MHC Class II complexes are endocytosed and recycle back to the surface. In the presence of interleukin-10 (IL-10), MARCH1 is upregulated. MARCH1 and MHC Class II molecules interact in recycling endosomes and the MARCH1-mediated ubiquitination of MHC Class II prevents recycling. MHC Class II molecules are redirected to lysosomal compartments where they are degraded.