TEIPP antigens for T-cell based immunotherapy of immune-edited HLA class I^low cancers

T-cell based immunotherapies through checkpoint blockade or adoptive transfer are effective treatments for a wide range of cancers like melanomas and lung carcinomas that harbor a high mutational load. The HLA class I and class II (HLA-I and HLA-II) presented neoantigens arise from genetic mutations in the cancerous cells and are ideal non-self targets for the T cell-based treatments. Although some cancer patients responded with complete regression, many others are irresponsive to checkpoint blockade treatments, or relapse after initial success. One of the mechanisms by which tumors evade T cell recognition is by acquiring deficiencies in the HLA-I antigen-processing pathway, leading to downregulation of HLA-I molecules at the cell surface and thereby creating an 'invisible' tumor phenotype. Interestingly, an alternative antigen repertoire arises on these HLA-I^low cancer cells. We refer to this alternative antigen repertoire as TEIPP: T cell epitopes associated with impaired peptide processing. TEIPP antigens are curious non-mutated peptides from housekeeping proteins that are not presented in homeostasis. In this review, for the first time we recapitulate all our published work on TEIPP antigens, including our recent understanding of the CD8 T cell repertoire. We are convinced that TEIPP-directed T cells will be valuable resources to target immune-edited tumors that have acquired resistance to checkpoint blockade therapy.