TAP1 deficiency reshapes tumor antigenicity and enables CD8 T cell targeting in colorectal cancer.

Loss of components of the antigen processing machinery, such as the transporter associated with antigen processing 1 (TAP1), is a frequent immune escape mechanism in colorectal cancer (CRC). Although TAP1 deficiency impairs classical antigen presentation, it may also generate alternative T cell epitopes associated with impaired peptide processing (TEIPP) exploitable for immunotherapy. We investigated whether human CRC harbors functional CD8 T cells targeting TAP1-deficient tumor cells. TAP1 expression was analyzed by immunohistochemistry in tumors from 193 CRC patients (156 microsatellite-stable [MSS] and 37 microsatellite-instable [MSI]). CD8 tumor-infiltrating lymphocytes (TILs) were expanded from 61 CRC samples and tested for reactivity against a TAP1-deficient CRC cell line. 26% of CRC tumors displayed reduced or absent TAP1 expression, with no significant association with overall survival. CD8 TILs reactive to TAP1-deficient tumor cells were detected in 46% of patients and their frequency correlated with low TAP1 expression, particularly in MSI CRCs. A CD8 T cell clone selectively recognized and efficiently killed TAP1-deficient CRC cells in an HLA-B∗07:02-restricted manner, inducing robust tumor cell apoptosis in both 2D cultures and 3D spheroid models. These findings demonstrate that TAP1 deficiency reshapes tumor antigenicity and enables CD8 T cell targeting in CRC, supporting the development of immunotherapies directed against TAP1-deficient tumors.