To determine the extent to which human intratumoral TCR repertoires are tumor reactive, Scheper and Kelderman et al. performed an unbiased functional analysis of TILs by isolating paired α/β TCRs, transducing them into donor cells, and testing for tumor reactivity. Intrinsic tumor reactivity was low or absent in ovarian and colorectal cancer samples, indicating that the vast majority of infiltrating T cells – even those expressing PD-1 – were functionally bystanders. The researchers suggest that incorporating and expanding on the tumor recognition potential of T cells could guide and enhance immunotherapy.
Infiltration of human cancers by T cells is generally interpreted as a sign of immune recognition, and there is a growing effort to reactivate dysfunctional T cells at such tumor sites(1). However, these efforts only have value if the intratumoral T cell receptor (TCR) repertoire of such cells is intrinsically tumor reactive, and this has not been established in an unbiased manner for most human cancers. To address this issue, we analyzed the intrinsic tumor reactivity of the intratumoral TCR repertoire of CD8(+) T cells in ovarian and colorectal cancer-two tumor types for which T cell infiltrates form a positive prognostic marker(2,3). Data obtained demonstrate that a capacity to recognize autologous tumor is limited to approximately 10% of intratumoral CD8(+) T cells. Furthermore, in two of four patient samples tested, no tumor-reactive TCRs were identified, despite infiltration of their tumors by T cells. These data indicate that the intrinsic capacity of intratumoral T cells to recognize adjacent tumor tissue can be rare and variable, and suggest that clinical efforts to reactivate intratumoral T cells will benefit from approaches that simultaneously increase the quality of the intratumoral TCR repertoire.