To improve the potency of a prostate TAA-specific TCR, Chen and Mao et al. screened for CDR hotspot mutations that could increase catch-bond formation and thus TCR sensitivity, without modifying TCR affinity (and the potential for off-target toxicity). Several variants increased TCR–pHLA bond lifetime, which correlated with TCR response to cognate peptide. These variants increased T cell proliferation, cytotoxicity, in vivo tumor efficacy, and effector/proliferative gene expression among TILs. Crystal structures and in silico modeling revealed alterations to water inclusion and hydrogen-bonding, supporting HLA, TCR, or peptide interactions.
Contributed by Alex Najibi
ABSTRACT: T cells are often weakly responsive to tumor self-antigens because of central tolerance, constraining their ability to eliminate tumors. We exploited mechanical force to engineer a weakly reactive T cell receptor (TCR) specific for a nonmutated tumor-associated antigen (TAA), prostatic acid phosphatase (PAP). We identified a catch-bonding "hotspot" whose mutation enhanced T cell activity by increasing TCR-pMHC (peptide-major histocompatibility complex) bond lifetime while preserving physiological affinities and antigen fine specificities. T cells expressing these engineered TCRs showed vastly superior expansion in the tumor, effector phenotypes, and tumor elimination. Crystal structures and molecular dynamics simulations revealed a single amino acid mutation at the catch-bond hotspot primes the TCR for peptide interaction through water reorganization at the TCR-pMHC interface. Catch-bond engineering is a viable biophysically based strategy for transforming tolerized antitumor T cells into potent TCR-T cell therapy killers.
Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (2) Department of Microbiology, Immunology, and Molecular Genetics,
Author Info: (1) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (2) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. (3) Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA. (4) Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA. (5) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (6) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (7) Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA. Department of Medicine, Center for Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA, USA. (8) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. (9) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. (10) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (11) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (12) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. (13) Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. (14) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (15) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. (16) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. (17) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. (18) Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. Department of Urology, UCLA, Los Angeles, CA, USA. (19) Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. (20) Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA, USA. Department of Medicine, Center for Biomedical Informatics Research, Stanford University School of Medicine, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, CA, USA. (21) Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, New York, NY, USA. (22) Department of Pathology, University of Utah School of Medicine, Salt Lake City, UT, USA. (23) Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles (UCLA), Los Angeles, CA, USA. Department of Molecular and Medical Pharmacology, UCLA, Los Angeles, CA, USA. Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, UCLA, Los Angeles, CA, USA. Parker Institute for Cancer Immunotherapy, UCLA, Los Angeles, CA, USA. Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA. Molecular Biology Institute, UCLA, Los Angeles, CA, USA. (24) Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. Parker Institute for Cancer Immunotherapy, Stanford University, Stanford, CA, USA. Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA.
