Identification of non-mutated neoantigens presented by TAP-deficient tumors

Abstract

Most T cell-based immunotherapies of cancer depend on intact antigen presentation by HLA class I molecules (HLA-I). However, defects in the antigen-processing machinery can cause downregulation of HLA-I, rendering tumor cells resistant to CD8 T cells. Previously, we demonstrated that a unique category of cancer antigens is selectively presented by tumor cells deficient for the peptide transporter TAP, enabling a specific attack of such tumors without causing immunopathology in mouse models. With a novel combinatorial screening approach, we now identify 16 antigens of this category in humans. These HLA-A*02:01 presented peptides do not derive from the mutanome of cancers, but are of "self" origin and therefore constitute universal neoantigens. Indeed, CD8 T cells specific for the leader peptide of the ubiquitously expressed LRPAP1 protein recognized TAP-deficient, HLA-I lymphomas, melanomas, and renal and colon carcinomas, but not healthy counterparts. In contrast to personalized mutanome-targeted therapies, these conserved neoantigens and their cognate receptors can be exploited for immune-escaped cancers across diverse histological origins.

Anti–PD-1 Induces M1 Polarization in the Glioma Microenvironment and Exerts Therapeutic Efficacy in the Absence of CD8 Cytotoxic T Cells

“…However, this contrasts with recent reports that levels of CD8 þ tumor-infiltrating lymphocytes are inversely correlated with glioma grade and are associated with long-term survival (55). Alternatively, the CD8 þ T-cell population may only have a role during the early stages of tumor development (56,57). Our primary hypothesis was that the elimination of the CD8 immune effector population would produce an increased incidence of high-grade gliomas resulting from the lack of immunologic recognition and control.…”

Combination of chemotherapy and PD-1 blockade induces T cell responses to tumor non-mutated neoantigens

“…However, despite the high mutational burden and the huge tumor T cell infiltration in several tumors including NSCLC, the frequencies of the related neoAg-specific T cells are relatively very low [20][21][22][23] . In the light of these evidences, it is possible that a consistent proportion of tumor-associated T cells may be specific to non-mutated (NM)-neoAgs generated by various forms of protein modifications occurring at post-transcriptional level, such as protein splicing 24 , dysregulated phosphorylation or glycosylation [25][26][27] , proteasome generation of spliced peptides 28 , peptide citrullination 29 , impaired peptide processing in TAP-deficient tumor cells 30 , or proteasomal degradation of defective ribosomal products (DRiPs) 31 . These NM-neoAgs may provide rational targets for cancer immunotherapy, because they should not be expressed or expressed at concentrations that are not enough to delete specific T cells in the thymus.…”

Future Challenges in Cancer Resistance to Immunotherapy

“…TAP deficiency has been demonstrated in many cancer types and shown to correlate with disease progression and clinical outcomes [79][80][81]. Interestingly, tumor cells with such antigen processing defects still express MHC-I molecules, which then present T cell epitopes associated with impaired peptide processing (TEIPP) [82][83][84]. Priming TEIPP-specific T cells with vaccines to overcome acquired immune resistance has been proposed as a treatment strategy for tumors with impaired TAP expression, and this approach has been proven effective in inhibiting the outgrowth of immune-escaped tumors in mice [85,86].…”