The immunopeptidomes of two transmissible cancers and their host have a common, dominant peptide motif

Abstract

Transmissible cancers are malignant cells that can spread between individuals of a population, akin to both a parasite and a mobile graft. The survival of the Tasmanian devil, the largest remaining marsupial carnivore, is threatened by the remarkable emergence of two independent lineages of transmissible cancer, devil facial tumour (DFT) 1 and devil facial tumour 2 (DFT2). To aid the development of a vaccine and to interrogate how histocompatibility barriers can be overcome, we analysed the peptides bound to major histocompatibility complex class I (MHC-I) molecules from Tasmanian devil cells and representative cell lines of each transmissible cancer. Here, we show that DFT1 + IFN-c and DFT2 cell lines express a restricted repertoire of MHC-I allotypes compared with fibroblast cells, potentially reducing the breadth of peptide presentation. Comparison of the peptidomes from DFT1 + IFNc, DFT2 and host fibroblast cells demonstrates a dominant motif, despite differences in MHC-I allotypes between the cell lines, with preference for a hydrophobic leucine residue at position 3 and position Ω of peptides. DFT1 and DFT2 both present peptides derived from neural proteins, which reflects a shared cellular origin that could be exploited for vaccine design. These results suggest that polymorphisms in MHC-I molecules between tumours and host can be 'hidden' by a common peptide motif, providing the potential for permissive passage of infectious cells and demonstrating complexity in mammalian histocompatibility barriers.

Expression of the Nonclassical MHC Class I, Saha-UD in the Transmissible Cancer Devil Facial Tumour Disease (DFTD)

“…Samples were amplified using primers specific for Saha-UD and a ribosomal protein, RPL13A , as a control (primers detailed in Table 2 ). Consistent with previous results, DFTD cell lines were positive for the Saha-UD heavy chain [ 30 , 32 , 33 ]. All DFTD primary tumours were positive by IHC and RT-PCR, confirming the results obtained with the UD(3) antibody.…”

“…The expression of the nonclassical Saha-UD heavy chain has previously been found in three DFTD cell lines [30,32,33], and this study provides the first evidence of Saha-UD expression in primary DFTD biopsies. Based on IHC staining, Saha-UD expression is common in DFTD tumours from different individuals.…”

“…Amino acid differences between the alleles are low, and few of these residues are predicted to interact with peptides or the T cell receptor [ 29 ]. Saha-UD , while it is in a separate phylogenetic clade [ 16 ], is closely related to the classical MHC-I genes [ 27 ] and binds to β 2 m [ 30 ]; therefore, it is hypothesised that Saha-UD molecules bind peptides for antigen presentation at the cell surface. Saha-UK is monomorphic [ 27 ]; therefore, its expression would not be expected to activate an immune response.…”

“…Saha-UK is monomorphic [ 27 ]; therefore, its expression would not be expected to activate an immune response. However, it is possible it does not bind to β 2 m [ 30 ] and is predicted to have a marsupial-specific function [ 16 ]. Due to the expression of Saha-UD in DFTD cell lines, its potential for peptide presentation, and its low polymorphism in the population, we investigated the expression of nonclassical Saha-UD in DFTD primary tumours as a mechanism for host immune evasion.…”

Understanding the constitutive presentation of MHC class I immunopeptidomes in primary tissues

“…In adaptive immunity, CD8 + T cells have the ability to eradicate abnormal cells through recognition of small peptide fragments presented by MHC (human leukocyte antigen (HLA) in humans) class I molecules. In this context, jawed vertebrates evolved an important antigen processing and presentation (APP) system capable of presenting thousands of different MHC class I peptides on the surface of virtually any nucleated cells ( Neefjes et al., 2011 ), and transmissible tumors could be a selective factor of APP evolution ( Dujon et al., 2020 ; Gastaldello et al., 2021 ). In mammals, around 200 different cell types are decorated by large repertoires of self-MHC-I-associated peptides, collectively referred to as the mammalian MHC-I immunopeptidome (MHC-I immunopeptidome) ( Caron et al., 2017 ; Vizcaíno et al., 2020 ).…”