A comprehensive profile of TCF1^(+)progenitor and TCF1−terminally exhausted PD-1^(+)CD8^(+)T cells in head and neck squamous cell carcinoma:implications for prognosis and immunotherapy

The heterogeneity of exhausted T cells(Tex)is a critical determinant of immune checkpoint blockade therapy efficacy.However,few studies have explored exhausted T cell subpopulations in human cancers.In the present study,we examined samples from two cohorts of 175 patients with head and neck squamous cell cancer(HNSCC)by multiplex immunohistochemistry(mIHC)to investigate two subsets of Tex,CD8+PD1+TCF1+progenitor exhausted T cells(TCF1+Texprog)and CD8+PD1+TCF1−terminally exhausted T cells(TCF1−Texterm).Moreover,fresh tumor samples from 34 patients with HNSCC were examined by flow cytometry and immunohistochemistry to further investigate their properties and cytotoxic capabilities and their correlation with regulatory T cells(Tregs)in the tumor immune microenvironment(TIME).mIHC and flow cytometry analysis showed that TCF1−Texterm represented a greater proportion of CD8+PD1+Tex than TCF1+Texprog in most patients.TCF1+Texprog produced abundant TNFα,while TCF1−Texterm expressed higher levels of CD103,TIM-3,CTLA-4,and TIGIT.TCF1−Texterm exhibited a polyfunctional TNFα+GZMB+IFNγ+phenotype;and were associated with better overall survival and recurrence-free survival.The results also indicated that larger proportions of TCF1−Texterm were accompanied by an increase in the proportion of Tregs.Therefore,it was concluded that TCF1−Texterm was the major CD8+PD1+Tex subset in the HNSCC TIME and that these cells favor patient survival.A high proportion of TCF1−Texterm was associated with greater Treg abundance.