Doorduijn et al. evaluated transferred CD8+ T cells specific for the TAP-independent Trh4 epitope, which is associated with impaired peptide processing (TEIPP), in the context of TAP-deficient MHC-Ilow tumors. Although Trh4-specific T cells did not infiltrate and were not activated by such tumors, the T cells were robustly activated by irradiated TAP-proficient tumor cells overexpressing Trh4. Prophylactically, this controlled tumor growth and increased survival in mice, indicating the potential of TEIPP antigen targeting in some immune-escaped tumors.

Cancers frequently evade immune-recognition by lowering peptide:MHC-I complexes on their cell surface. Limited peptide supply due to TAP-deficiency results in such MHC-I(low) immune-escape variants. Previously, we reported on a category of TAP-independent self-peptides, called TEIPP, with selective presentation by these tumors. Here we demonstrate that in contrast to T cells specific for conventional tumor antigens, TEIPP-directed T cells remain naive in mice bearing immune-escaped tumors. This unaffected state was caused by low levels of MHC-I on the tumors and the failure to cross-present low levels of antigenic protein by host APCs. Importantly, increased levels of MHC-I, antigen or co-stimulation resulted in potent activation of TEIPP-specific T cells via direct presentation. Genetic knockdown by CRISPR/Cas9 technology of the relevant MHC-I allele in tumor cells indeed abrogated T cell activation. Vaccine-mediated priming of TEIPP-specific T cells induced efficient homing to MHC-I(low) tumors and subsequently protected mice against outgrowth of their MHC-I(low) tumor. Thus, our data open up the search of TEIPP-specific T cells in cancer patients to explore their application against MHC-I(low) tumor cells.

Author Info: (1) Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, the Netherlands. (2) Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, the

Author Info: (1) Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, the Netherlands. (2) Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, the Netherlands. (3) Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, the Netherlands. (4) Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, the Netherlands. (5) Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, the Netherlands. (6) Department of Medical Oncology, Leiden University Medical Center (LUMC), Leiden, the Netherlands.

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