Evolution and modulation of antigen-specific T cell responses in melanoma patients

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 () and Satu Mustjoki ()
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Jani Huuhtanen: University of Helsinki
Liang Chen: Stanford University
Emmi Jokinen: Aalto University
Henna Kasanen: University of Helsinki
Tapio Lönnberg: University of Turku and Åbo Akademi University
Anna Kreutzman: University of Helsinki
Katriina Peltola: iCAN Digital Precision Cancer Medicine Flagship
Micaela Hernberg: Helsinki University Hospital Comprehensive Cancer Center
Chunlin Wang: Stanford University
Cassian Yee: The University of Texas MD Anderson Cancer Center
Harri Lähdesmäki: Aalto University
Mark M. Davis: Stanford University
Satu Mustjoki: University of Helsinki

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-33720-z

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