Exposure to Melan-A/MART-126-35 tumor epitope specific CD8+T cells reveals immune escape by affecting the ubiquitin-proteasome system (UPS)

Abstract

Efficient processing of target antigens by the ubiquitin-proteasome-system (UPS) is essential for treatment of cancers by T cell therapies. However, immune escape due to altered expression of IFN-γ-inducible components of the antigen presentation machinery and consequent inefficient processing of HLA-dependent tumor epitopes can be one important reason for failure of such therapies. Here, we show that short-term co-culture of Melan-A/MART-1 tumor antigen-expressing melanoma cells with Melan-A/MART-126-35-specific cytotoxic T lymphocytes (CTL) led to resistance against CTL-induced lysis because of impaired Melan-A/MART-126-35 epitope processing. Interestingly, deregulation of p97/VCP expression, which is an IFN-γ-independent component of the UPS and part of the ER-dependent protein degradation pathway (ERAD), was found to be essentially involved in the observed immune escape. In support, our data demonstrate that re-expression of p97/VCP in Melan-A/MART-126-35 CTL-resistant melanoma cells completely restored immune recognition by Melan-A/MART-126-35 CTL. In conclusion, our experiments show that impaired expression of IFN-γ-independent components of the UPS can exert rapid immune evasion of tumor cells and suggest that tumor antigens processed by distinct UPS degradation pathways should be simultaneously targeted in T cell therapies to restrict the likelihood of immune evasion due to impaired antigen processing.

B cells and the humoral response in melanoma: The overlooked players of the tumor microenvironment

“…As melanoma cells may be able to escape host immune responses, 115-117 the B cell repertoire and antibodies expressed in the patient context may not be effective enough to confer tumor clearance. Antibody isotypes such as IgG4 and IgA may regulate immune effector functions and support immune evasion.…”

Coevolution of Leukemia and Host Immune Cells in Chronic Lymphocytic Leukemia

“…Efficient processing of tumor epitopes by cellular proteolytic intermediates is essential for the generation of an effective antitumor cytotoxic response. Impaired antigen processing due to deregulation of the proteasomal degradation has been consistently revealed as an immune escape mechanism in tumor cells (Sun et al 2002; Guillaume et al 2012; Ebstein et al 2016). One of the most frequent causes of immune escape in human tumors is defects in the antigen-presenting machinery due to HLA class I molecule downregulation or loss (Restifo et al 1993; Seliger et al 2001, 2002; Paschen et al 2006), low affinity peptide-MHC interactions (Engels et al 2013), and recently, a greater than expected frequency of somatic mutations in class I HLA genes, predicted to be loss-of-function, was discovered across cancers, associated with upregulation of signatures of cytolytic activity characteristic of tumor infiltration by effector lymphocytes.…”

Methods for detecting co-mutated pathways in cancer samples to inform treatment selection

“…In colorectal cancer, we identified significantly co-occurring mutations in the proteasome and apoptosis pathways. Several reports have implied that mutations in the proteasome pathway or the apoptosis pathway play a role in evading immune surveillance (14,15), but to the best of our knowledge this is the first study which implies that co-mutation of these pathways, at least in colorectal cancer, may lead to enhanced immune evasion. We hypothesized that these two pathways synergistically protect tumors from the immune system as they are key for degradation and immune system presentation of neoantigens, and for immunity mediated apoptosis.…”

“…Our method was also applied to six different types of cancer from the TCGA project and we identified unique co-mutated pathways in these cancers. In colorectal cancer, we detected co-occurrence of mutations in the proteasome pathway and the extrinsic apoptosis pathway, suggesting a potential synergistic mechanism for immune evasion due to defects in the apoptosis pathway (14) and decreased neoantigen presentation resulting from defects in the proteasome pathway (15).…”