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

Abstract

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.

BASP1 is a prognostic biomarker associated with immunotherapeutic response in head and neck squamous cell carcinoma

“…Upregulation of immune checkpoint inhibitors (e.g., PD-1/PD-L1) attenuates the cytolytic activity of CD8 + T cells in HNSCC (45). Here, we found that, although there was no significant difference in the total immune score between BASP1 high and BASP1 low tumors, BASP1 high ones exhibited reduced and exhausted cytotoxic CD8 + T cells, which have critical influence on immune checkpoint blockade therapy efficacy (46). Furthermore, the increased immune checkpoint inhibitors and reduced immune checkpoint stimulators in the BASP1 high group also indicated an exhausted environment (47).…”

Vinorelbine and Intermittent Cyclophosphamide Sensitize an Aggressive Myc-Driven B-Cell Lymphoma to Anti-PD-1 by an Immunological Memory Effective against Tumor Re-Challenge

“…We and others have previously demonstrated that anti-PD-1 favors the selection of progenitor-exhausted T cells, with crucial effects over tumor growth [ 4 , 5 , 6 ]. Progenitor-exhausted T cells are defined to be Tcf1 + [ 12 ], whereas terminally exhausted T cells, which have poor anticancer function, are defined as PD-1 + Tim3 + [ 13 ].…”

Pertussis toxin-induced inhibition of Wnt/β-catenin signaling in dendritic cells promotes an autoimmune response in experimental autoimmune uveitis

“…We also observed that decreased β-catenin activity inhibited the expression of Wnt-associated genes, such as Sox9, Axin2, Tcf1, and Lef1. Transcription factors TCF1 and LEF1 could regulate the proliferation, apoptosis, and function of DCs, Treg cells, and CD8 + T cells [38][39][40]. Sox9 regulated by Wnt/β-catenin plays a key role in the polarization of macrophages [41].…”