Huuhtanen et al. analyzed scRNA + TCR-seq, paired bulk-RNA, and TCRβ-seq from melanoma biopsies to understand antigen-specific immune responses. Melanoma-associated antigen (MAA)-specific TCRs were restricted to individuals, but TCR motifs were shared. Anti-MAA clonotypes were enriched in melanoma patients and included both stem-like (TCF7+) and exhausted T cells. ICI treatment reversed the exhaustion and expanded anti-MAA clonotypes in responders. Absence of a dominating anti-MART1 clone (>1% repertoire) in the tumor was associated with better survival in primary melanoma, whereas clonal replacement was not associated with response to ICI.
Contributed by Shishir Pant
ABSTRACT: Analyzing antigen-specific T cell responses at scale has been challenging. Here, we analyze three types of T cell receptor (TCR) repertoire data (antigen-specific TCRs, TCR-repertoire, and single-cell RNA + TCRαβ-sequencing data) from 515 patients with primary or metastatic melanoma and compare it to 783 healthy controls. Although melanoma-associated antigen (MAA) -specific TCRs are restricted to individuals, they share sequence similarities that allow us to build classifiers for predicting anti-MAA T cells. The frequency of anti-MAA T cells distinguishes melanoma patients from healthy and predicts metastatic recurrence from primary melanoma. Anti-MAA T cells have stem-like properties and frequent interactions with regulatory T cells and tumor cells via Galectin9-TIM3 and PVR-TIGIT -axes, respectively. In the responding patients, the number of expanded anti-MAA clones are higher after the anti-PD1(+anti-CTLA4) therapy and the exhaustion phenotype is rescued. Our systems immunology approach paves the way for understanding antigen-specific responses in human disorders.
Author Info: (1) Translational Immunology Research Program, University of Helsinki, Helsinki, Finland. Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Cente
Author Info: (1) Translational Immunology Research Program, University of Helsinki, Helsinki, Finland. Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland. iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland. Department of Computer Science, Aalto University, Espoo, Finland. (2) Department of Immunology and Microbiology, Stanford University, Stanford, CA, USA. Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA. (3) Department of Computer Science, Aalto University, Espoo, Finland. (4) Translational Immunology Research Program, University of Helsinki, Helsinki, Finland. Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland. iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland. (5) Turku Bioscience Centre, University of Turku and bo Akademi University, Turku, Finland. InFLAMES Research Flagship Center, University of Turku, Turku, Finland. (6) Translational Immunology Research Program, University of Helsinki, Helsinki, Finland. Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland. iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland. (7) iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland. Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland. (8) Department of Oncology, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland. (9) Department of Immunology and Microbiology, Stanford University, Stanford, CA, USA. Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA. (10) Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Department of Computer Science, Aalto University, Espoo, Finland. (12) Department of Immunology and Microbiology, Stanford University, Stanford, CA, USA. mmdavis@stanford.edu. Institute for Immunity, Transplantation and Infection, Stanford University School of Medicine, Stanford, CA, USA. mmdavis@stanford.edu. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. mmdavis@stanford.edu. (13) Translational Immunology Research Program, University of Helsinki, Helsinki, Finland. satu.mustjoki@helsinki.fi. Hematology Research Unit Helsinki, Helsinki University Hospital Comprehensive Cancer Center, Helsinki, Finland. satu.mustjoki@helsinki.fi. iCAN Digital Precision Cancer Medicine Flagship, Helsinki, Finland. satu.mustjoki@helsinki.fi. Department of Clinical Chemistry and Hematology, University of Helsinki, Helsinki, Finland. satu.mustjoki@helsinki.fi.
