T cell factor 1 (TCF-1) defines T cell differentiation in colorectal cancer

The presence of precursor to exhausted (T_pex) CD8⁺ T cells is important to maintain robust immunity following treatment with immune checkpoint inhibition (ICI). Impressive responses to ICI are emerging in patients with stage II-III mismatch repair (MMR)-deficient (dMMR) colorectal cancer (CRC). We found 64% of dMMR and 15% of mismatch repair-proficient (pMMR) stage III CRCs had a high frequency of tumor infiltrating lymphocytes (TIL-hi). Furthermore, expression of TCF-1 <i>(Tcf7)</i> by CD8⁺ T cells predicted improved patient prognosis and T_pex cells (CD3⁺CD8⁺TCF-1⁺PD-1⁺) were abundant within lymphoid aggregates of stage III CRCs. In contrast, CD3⁺CD8⁺TCF-1^-PD-1⁺ cells were more abundant at the invasive front and tumor core, while γδ T cells were equally abundant in all tumor areas. Interestingly, no differences in the frequency of T_pex cells were observed between TIL-hi dMMR and TIL-hi pMMR CRCs. Therefore, T_pex cell function and ICI response rates in TIL-hi CRC warrants further investigation.