Pinpointing the tumor-specific T cells via TCR clusters
Mikhail M Goncharov, Ekaterina A Bryushkova, Nikita I Sharaev, Valeria D Skatova, Anastasiya M Baryshnikova, George V Sharonov, Vadim Karnaukhov, Maria T Vakhitova, Igor V Samoylenko, Lev V Demidov, Sergey Lukyanov, Dmitriy M Chudakov, Ekaterina O Serebrovskaya
Abstract
Adoptive cell transfer (ACT) is a promising approach to cancer immunotherapy, but its efficiency fundamentally depends on the extent of tumor-specific T cell enrichment within the graft. This can be estimated via activation with identifiable neoantigens, tumor-associated antigens (TAAs), or living or lysed tumor cells, but these approaches remain laborious, time-consuming, and functionally limited, hampering clinical development of ACT. Here, we demonstrate that homology cluster analysis of T cell receptor (TCR) repertoires efficiently identifies tumor-reactive TCRs allowing to: (1) detect their presence within the pool of tumor-infiltrating lymphocytes (TILs); (2) optimize TIL culturing conditions, with IL-2 low /IL-21/anti-PD-1 combination showing increased efficiency; (3) investigate surface marker-based enrichment for tumor-targeting T cells in freshly isolated TILs (enrichment confirmed for CD4 + and CD8 + PD-1 + /CD39 + subsets), or re-stimulated TILs (informs on enrichment in 4-1BB-sorted cells). We believe that this approach to the rapid assessment of tumor-specific TCR enrichment should accelerate T cell therapy development.