Transcriptomic signatures of tumors undergoing T cell attack

Aishwarya Gokuldass, Aimilia Schina, Martin Lauss, Katja Harbst, Christopher Aled Chamberlain, Arianna Draghi, Marie Christine Wulff Westergaard, Morten Nielsen, Krisztian Papp, Zsofia Sztupinszki, Istvan Csabai, Inge Marie Svane, Zoltan Szallasi, Göran Jönsson, Marco Donia

1 Citationer (Scopus)

Abstrakt

BACKGROUND: Studying tumor cell-T cell interactions in the tumor microenvironment (TME) can elucidate tumor immune escape mechanisms and help predict responses to cancer immunotherapy.

METHODS: We selected 14 pairs of highly tumor-reactive tumor-infiltrating lymphocytes (TILs) and autologous short-term cultured cell lines, covering four distinct tumor types, and co-cultured TILs and tumors at sub-lethal ratios in vitro to mimic the interactions occurring in the TME. We extracted gene signatures associated with a tumor-directed T cell attack based on transcriptomic data of tumor cells.

RESULTS: An autologous T cell attack induced pronounced transcriptomic changes in the attacked tumor cells, partially independent of IFN-γ signaling. Transcriptomic changes were mostly independent of the tumor histological type and allowed identifying common gene expression changes, including a shared gene set of 55 transcripts influenced by T cell recognition (Tumors undergoing T cell attack, or TuTack, focused gene set). TuTack scores, calculated from tumor biopsies, predicted the clinical outcome after anti-PD-1/anti-PD-L1 therapy in multiple tumor histologies. Notably, the TuTack scores did not correlate to the tumor mutational burden, indicating that these two biomarkers measure distinct biological phenomena.

CONCLUSIONS: The TuTack scores measure the effects on tumor cells of an anti-tumor immune response and represent a comprehensive method to identify immunologically responsive tumors. Our findings suggest that TuTack may allow patient selection in immunotherapy clinical trials and warrant its application in multimodal biomarker strategies.

OriginalsprogEngelsk
TidsskriftCancer Immunology and Immunotherapy
Vol/bind71
Udgave nummer3
Sider (fra-til)553-563
Antal sider11
ISSN0340-7004
DOI
StatusUdgivet - mar. 2022

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