1. Evolution and modulation of antigen-specific T cell responses in melanoma patients
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Jani Huuhtanen, Liang Chen, Emmi Jokinen, Henna Kasanen, Tapio Lönnberg, Anna Kreutzman, Katriina Peltola, Micaela Hernberg, Chunlin Wang, Cassian Yee, Harri Lähdesmäki, Mark M. Davis, Satu Mustjoki, Department of Computer Science, Stanford University, Professorship Lähdesmäki Harri, University of Helsinki, University of Turku, ICAN Digital Precision Cancer Medicine Flagship, University of Texas MD Anderson Cancer Center, Computer Science Professors, Aalto-yliopisto, Aalto University, TRIMM - Translational Immunology Research Program, HUS Comprehensive Cancer Center, Hematologian yksikkö, Digital Precision Cancer Medicine (iCAN), HUSLAB, Department of Oncology, Department of Clinical Chemistry and Hematology, and Clinicum more...
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Tumor-antigens ,Multidisciplinary ,Receptors, Antigen, T-Cell, alpha-beta ,Signatures ,3122 Cancers ,Receptors, Antigen, T-Cell ,General Physics and Astronomy ,Expression ,General Chemistry ,Repertoires ,General Biochemistry, Genetics and Molecular Biology ,Humans ,RNA ,Landscape ,Therapy ,Immunotherapy ,3111 Biomedicine ,Hepatitis A Virus Cellular Receptor 2 ,Melanoma ,Features - Abstract
Funding Information: We are deeply grateful to all patients who participated in the study and generously contributed samples. We acknowledge the computational resources provided by the Aalto Science-IT project and all the personnel in the Hematology Research Unit Helsinki for insightful conversations. We especially thank Dr. Nathalie Labarriere for providing information of MAA-specific TCR sequences of their study; Dr. Michael Durante and Dr. J. William Harbor for providing information related to their study; Dr. Olli Dufva for his help with interpreting the data. We additionally acknowledge Ms. Lotta Länsman for providing administrative advice. This study was supported by the European Research Council (Project: M-IMM 647355)(SM), Academy of Finland (314442, S.M., H.L. and 335527 S.M.), Sigrid Juselius Foundation (S.M.), Signe and Ane Gyllenberg Foundation (S.M.), Helsinki Institute for Life Science (S.M.), Cancer Foundation Finland (S.M.) and State funding for the University-level Health Research in Finland(S.M.). J.H. was supported by Finnish Hematology Association, Blood Disease Research Foundation, Helsinki Institute for Life Science, Biomedicum Helsinki Foundation, Finnish Medical Foundation, K. Albin Johansson Foundation, Kaute Foundation, Suomalais-Norjalainen Lääketieteen Säätiö, and Emil Aaltonen Foundation. T.L. was supported by Academy of Finland (Decision 311081). Funding Information: M.H. has received honoraria from Pierre Fabre, Novartis, Bristol-Myers Squibb (B.M.S.), Merck Sharp & Dohme (M.S.D.), Roche, Amgen, Sanofi, and Incyte. S.M. has received honoraria and research funding from B.M.S. and research funding from Novartis and Pfizer. M.M.D. has received honoraria and/or equity from Amgen, Chugai, Vir, IGMS, Janux, A2, 3T, Mozart, Red Tree, and research funding from Sanofi. The remaining authors declare no competing interests. Publisher Copyright: © 2022, The Author(s). 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. more...
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- 2022
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