Multifactorial remodeling of the cancer immunopeptidome by interferon gamma

Abstract

IFNγ alters the immunopeptidome presented on HLA class I (HLA-I), and its activity on cancer cells is known to be important for effective immunotherapy responses. We performed proteomic analyses of untreated and IFNγ-treated colorectal cancer patient-derived organoids (PDOs) and combined this with transcriptomic and HLA-I immunopeptidomics data to dissect mechanisms that lead to remodeling of the immunopeptidome through IFNγ. IFNγ-induced changes in the abundance of source proteins, switching from the constitutive- to the immunoproteasome, and differential upregulation of different HLA alleles explained some, but not all, observed peptide abundance changes. By selecting for peptides which increased or decreased the most in abundance, but originated from proteins with limited abundance changes, we discovered that the amino acid composition of presented peptides also influences whether a peptide is up- or downregulated on HLA-I through IFNγ. The presence of proline within the peptide core was most strongly associated with peptide downregulation. This was validated in an independent dataset. Proline substitution in relevant core positions did not influence the predicted HLA-I binding affinity or stability, indicating that proline effects on peptide processing may be most relevant. Understanding the multiple factors that influence the abundance of peptides presented on HLA-I in the absence or presence of IFNγ is important to identify the best targets for antigen-specific cancer immunotherapies such as vaccines or T-cell receptor engineered therapeutics.

The Proteasome Activator PA200/PSME4: An Emerging New Player in Health and Disease

“…However, the early studies have refuted this assumption by showing that the transcription rate of PSME4 remained unchanged in DC following exposure to various maturation-inducing agents, including LPS, Poly-IC, CD40L, a combination of TNF-α, IL-1β, IL-6, and PGE2 [ 78 ]. This notion is further supported by recent work showing that IFN-γ fails to upregulate PA200 in colorectal cancer patient-derived organoids [ 79 ]. The reason for the lack of responsiveness of PA200/PSME4 to IFN signaling and/or microbial stimuli is unclear, but may be related to epigenetic processes.…”