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.
Highlights
Therapeutic advances in immune checkpoint blockade (ICB) therapy have rapidly emerged in the past few years, yielding gratifying results related to the treatment of several kinds of tumors
tumor immune microenvironment (TIME) A five-color multiplex immunohistochemistry (mIHC) scheme that included anti-PanCK, antiCD8, anti-programmed death-1 (PD-1), anti-TCF1, and DAPI was production and phenotypic characteristics in head and neck squamous cell cancer (HNSCC) Based on the different prognostic values of TCF1+Texprog and TCF1−Texterm, we investigated the cytokine production and developed to comprehensively profile the spatial distribution of TCF1+Texprog and TCF1−Texterm
We found that the mean fluorescence intensity (MFI) of The flow immunoglobulin and mucin-domain containing-3 (TIM-3), consistent toxic T lymphocyte antigen 4 (CTLA-4), and T cell immunoglobulin and ITIM domain (TIGIT) was stronger in TCF1−Texterm, but there was no significant difference in the expression of lymphocyte activation gene-3 (LAG-3) (Fig. 3g, h)
Summary
Therapeutic advances in immune checkpoint blockade (ICB) therapy have rapidly emerged in the past few years, yielding gratifying results related to the treatment of several kinds of tumors. The programmed death-1 (PD-1)-blocking antibody nivolumab was the first immune checkpoint inhibitor approved by the United States Food and Drug Administration (FDA) for metastatic head and neck squamous cell cancer (HNSCC), receiving approval in 2016 on the basis of the results of the CheckMate 141 trial.[1] due to the complex components of the tumor immune microenvironment (TIME), the overall response rates to ICB therapies for HNSCC range from just 19 to 33%.1–3. The HNSCC TIME is populated by dysfunctional immune cells, inhibitory cytokines, and exosomes carrying suppressive ligands.[4,5] Among all immune cell phenotypes, cytotoxic T cell exhaustion is a hallmark of many cancers and strongly affects ICB therapy.
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