Elucidating properties of T cell receptors that govern pancreatic cancer immunotherapy response

Abstract public domain (NIH RePORTER)

ABSTRACT Pancreatic ductal adenocarcinoma (PDA) is an exceptionally lethal cancer for which most patients lack durable therapies. Its pronounced therapeutic resistance is due in part from a highly fibroinflammatory and immunosuppressive tumor microenvironment. Although immunotherapies have transformed the management of many cancers, PDA remains largely refractory. These therapies rely on activating tumor-reactive T cells capable of trafficking into tumors, recognizing antigen, killing malignant cells, and eliciting clinical responses. Yet even in cancers that initially respond to immunotherapy, long-term durability is often limited. This project addresses a critical gap in our understanding of how T cells function within the pancreatic tumor microenvironment and respond to immunotherapy. Each T cell expresses a unique T cell receptor (TCR), which exhibits exquisite specificity for peptide-MHC (pMHC). The human T cell repertoire encompasses billions of TCRs, a diversity essential for defense against pathogens and abnormal cells. Historically, efforts to generate TCR-engineered T cell therapies have focused on isolating and affinity-enhancing TCRs that bind strongly to pMHC tetramers. However, our data indicate that this approach has limitations. The specific features of TCR:pMHC interactions that determine antitumor fitness, durability, and immunotherapy responsiveness in PDA remain poorly defined. We show that TCRs undetectable by conventional pMHC tetramer staining can dramatically outcompete tetramer-positive counterparts within the same pancreatic tumor microenvironment, a difference that becomes 25-fold more pronounced after immunotherapy. Strikingly, the most potent tetramer-negative TCR forms significantly longer bond lifetimes with its cognate pMHC under increasing force, demonstrating a robust “catch bond” and in contrast to tetramer-positive TCRs. This finding highlights an underexplored principle in tumor immunology: TCR:pMHC bond lifetime under force, independent of traditional affinity metrics, governs TCR signaling and functional output. Here, we will test the hypothesis that bond lifetime between tumor-specific TCR and pMHC dictates T-cell persistence and antitumor efficacy during immunotherapy through three aims: 1) Define the properties of pancreatic tumor-specific TCRs recognizing the same pMHC that determine T cell responsiveness, 2) Determine how TCR:pMHC recognition shapes T cell behavior in vivo; and 3) Engineer human TCRs with enhanced antitumor potency by modulating bond lifetime. Animal models are required to investigate how antigen-specific T cells function, differentiate, and interact with the tumor microenvironment during PDA progression and immunotherapy. These studies are necessary to identify mechanisms and develop therapeutic approaches that can be translated to improve outcomes for patients with this lethal disease. By elucidating how bond lifetime influences T cell function during immunotherapy, this work will inform TCR selection and combinatorial therapeutic strategies for patients with solid tumors, ultimately driving meaningful advances in the field.

Public health relevance public domain (NIH RePORTER)

NARRATIVE This project aims to elucidate traits of T cell receptors that promote T cell fitness and immunotherapy response in pancreatic cancer. Our work will guide TCR selection and combinatorial strategies to enhance T cell therapies against solid tumors, ultimately yielding a significant impact for the field.