Exploring TCR/CAR antagonism from a functional and mechanistic perspective

Thesis

Chimeric antigen receptor (CAR) T cells have transformed therapy for blood cancers, yet their limited specificity has hindered success in solid tumors. In contrast, endogenous T cell receptor (TCR)–bearing T cells can distinguish neoantigen-positive tumor cells from healthy self-tissues, but typically lack robust antitumor potency. Here, we engineered a customizable robotic platform, named the IMMUNOtron, and a high throughput data processing pipeline, named plateypus, to decipher how these two receptors interacted with one another. We utilized the IMMUNOtron and plateypus to systematically stimulate CAR T cells that co-expressed a TCR and a CAR with different combinations of TCR and CAR signal strengths. These quantitative measurements allowed us to discover that strong TCR–antigen engagements potentiated CAR signaling, whereas weak TCR–antigen interactions suppressed activation. A mathematical model recapitulated this TCR/CAR crosstalk and guided the design of dual-receptor AEBS (Antagonism Enforced Breaking System) T cells recognizing neoantigens via the TCR and HER2 ligands via the CAR. When tested in a humanized solid-tumor mouse model, these dual TCR/CAR T cells showed superior antitumor efficacy with minimal damage to healthy tissues compared with conventional CAR and TCR T cells. A clinically translatable version of this construct that expressed a p53-R175H targeting TCR was able to display similar behavior even with endogenous levels of ligand. Exploiting intracellular crosstalk between immune receptors therefore could offer a path towards more precise and safer cancer immunotherapies.

Authors: Achar, S

• DOI: 10.5287/ora-gp59dw4ee
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: TCR; T cell; antagonism; cancer; CAR-T; antigen; immunotherapy
• Subjects: Immunology; Bioinformatics; Immunotherapy