TIL are heterogeneous and include tumor-reactive and non-tumor reactive
T cells. Non-tumor reactive, bystander T cells appear functional and cytotoxic,
express high levels of TCF1 and no or low levels of inhibitory receptors (IR).
Tumor-induced T cell dysfunction is progressive and various dysfunctional states
exist depending on spatiotemporal factors including antigen burden and duration
of tumor antigen exposure. Tumor-specific T cells are initially TCF1+ but with
time lose TCF1 expression, become TCF1 low/neg, and upregulate
numerous inhibitory receptors (IR+++). It is currently not known if TCF1+
tumor-specific T cells represent a stable, self-renewing population. We
hypothesize that, in human tumors, as seen in autochthonous tumor mouse models,
reprogrammable and non-reprogrammable dysfunctional T cells may be present.
Tumor-reactive T cells are also found in the periphery (e.g. blood and lymph
nodes) and typically do not have the ‘exhausted’ phenotype, and
these T cells maybe the population most amenable to immunotherapy.