Implications of Antigen Selection on T Cell-Based Immunotherapy

Abstract

Many immunotherapies rely on CD8+ effector T cells to recognize and kill cognate tumor cells. These T cell-based immunotherapies include adoptive cell therapy, such as CAR T cells or transgenic TCR T cells, and anti-cancer vaccines which expand endogenous T cell populations. Tumor mutation burden and the choice of antigen are among the most important aspects of T cell-based immunotherapies. Here, we highlight various classes of cancer antigens, including self, neojunction-derived, human endogenous retrovirus (HERV)-derived, and somatic nucleotide variant (SNV)-derived antigens, and consider their utility in T cell-based immunotherapies. We further discuss the respective anti-tumor/anti-self-properties that influence both the degree of immunotolerance and potential off-target effects associated with each antigen class.

A Novel Cell-based Luciferase Reporter Platform for the Development and Characterization of T-Cell Redirecting Therapies and Vaccine Development

“…We also tested whether TCR-KO reporter cells could be used to detect the T-cell response from nucleic acidderived antigens. TCR-KO (CD8 + ) cells stably expressing an HPV16 E6 [29][30][31][32][33][34][35][36][37][38] -specific TCR (HPV16 E6 TCR reporter cells) showed dose-dependent reporter response when being incubated with A375 cells transiently transfected with different amount of DNA plasmid encoding the full-length HPV16 E6 protein (Fig. 6E).…”

“…Therefore, TCR-KO (CD4 + ) reporter cells are best suited for measuring TCR activation by MHCII-restricted antigens. Next, we set off to develop a TCR-KO CD8 + reporter cell line for TCR-based therapies targeting MHCI-restricted epitopes 37. First, we knocked out CD4 in the TCR-KO (CD4 + ) reporter cells, then engineered the CD4 − population to stably express CD8αβ [Fig.…”

“…Next, we set off to develop a TCR-KO CD8 + reporter cell line for TCR-based therapies targeting MHCI-restricted epitopes. 37 First, we knocked out CD4 in the TCR-KO (CD4 + ) reporter cells, then engineered the CD4 − population to stably express CD8αβ [Fig. 3 A, TCR-KO (CD8 + )].…”

Antigens Expressed by Breast Cancer Cells Undergoing EMT Stimulate Cytotoxic CD8+ T Cell Immunity

“…Recent analyses of the human transcriptome have shown that alternative splicing is increased in cancer samples compared to matched normal samples by up to 30% [ 21 , 52 ]. Although the bioinformatics suggest that these neojunctions may in fact be good targets for immunotherapies, it has yet to be determined whether antigens derived from these neojunctions (defined as exon-exon junctions derived from alternative splicing found predominately in tumor samples) elicit antitumor T cell responses.…”

“…In this study, we considered neoantigens generated by miR-200c-mediated alterations in gene expression and gene splicing due to altered expression of splicing factors (SNV and neojunction-derived neoantigens, respectively) in EO771 cells following miR-200c restoration as a means to target mesenchymal cells and found mesenchymal-associated antigen elicited superior cytotoxicity against epithelial counterparts. The study highlights the extreme complexity involved in accurate prediction of neojunction-derived antigens resulting in low validation rates [ 52 ]. Thus, translating neojunction-derived antigens to anticancer immunotherapy will require additional layers of computational biology combined with new and existing technologies, including some that have long been a benefit to antigen discovery, such as mass spectrometry.…”