T cell receptors employ diverse strategies to target a p53 cancer neoantigen

Daichao Wu,Ragul Gowathaman,Brian G Pierce,Roy A Mariuzza

doi:10.1016/j.jbc.2022.101684

Abstract

Adoptive cell therapy with tumor-specific T cells can mediate durable cancer regression. The prime target of tumor-specific T cells are neoantigens arising from mutations in self-proteins during malignant transformation. To understand T cell recognition of cancer neoantigens at the atomic level, we studied oligoclonal T cell receptors (TCRs) that recognize a neoepitope arising from a driver mutation in the p53 oncogene (p53R175H) presented by the major histocompatibility complex class I molecule HLA-A2. We previously reported the structures of three p53R175H-specific TCRs (38-10, 12-6, and 1a2) bound to p53R175H and HLA-A2. The structures showed that these TCRs discriminate between WT and mutant p53 by forming extensive interactions with the R175H mutation. Here, we report the structure of a fourth p53R175H-specific TCR (6-11) in complex with p53R175H and HLA-A2. In contrast to 38-10, 12-6, and 1a2, TCR 6-11 makes no direct contacts with the R175H mutation, yet is still able to distinguish mutant from WT p53. Structure-based in silico mutagenesis revealed that the 60-fold loss in 6-11 binding affinity for WT p53 compared to p53R175H is mainly due to the higher energetic cost of desolvating R175 in the WT p53 peptide during complex formation than H175 in the mutant. This indirect strategy for preferential neoantigen recognition by 6-11 is fundamentally different from the direct strategies employed by other TCRs and highlights the multiplicity of solutions to recognizing p53R175H with sufficient selectivity to mediate T cell killing of tumor but not normal cells.

Highlights

Adoptive cell therapy (ACT) with tumor-specific T cells can promote durable regression of diverse cancers, including metastatic melanoma, colon, bile duct, cervix, and breast cancers [1,2,3,4,5]
T cell receptor (TCR) 6-11 discriminates between mutant and wild-type p53 peptides TCR 6-11 was isolated by screening tumor-infiltrating lymphocyte (TIL) from patients with metastatic colorectal cancer for reactivity towards the mutated p53R175H neoantigen [16]
Recognizes the p53R175H neoepitope using TRAV6 and TRAJ43 for the chain and TRBV11-2 and TRBJ2-2 for the chain. These gene segments are completely different from those utilized by TCRs 12-6, 38-10, and 1a2, which recognize the same p53R175H–HLA-A2 ligand as 6-11 (Table 1)

Summary

Introduction

Adoptive cell therapy (ACT) with tumor-specific T cells can promote durable regression of diverse cancers, including metastatic melanoma, colon, bile duct, cervix, and breast cancers [1,2,3,4,5]. The immunogenicity of p53 mutations in cancer patients has been demonstrated by the detection of T cell responses against several p53 neoantigens, most notably R175H in which arginine at position 175 is replaced by histidine [15, 16] This driver mutation is the most frequently observed mutation in TP53, as well as the most common mutation in any tumor suppressor gene [17]. In sharp contrast to 12-6, 38-10, and 1a2, TCR 6-11 makes no contacts with the R175H mutation, yet is able to distinguish mutant from wild-type p53 These structures demonstrate that there are multiple distinct solutions to recognizing the p53R175H neoepitope with sufficient on-target affinity and specificity to mediate killing of tumor cells expressing mutant p53 without affecting normal cells expressing wild-type p53, a critical consideration for avoiding adverse clinical events in ACT due to off-target TCR recognition [20]

Results

Discussion

Experimental Procedures

B RU 250