A Comprehensive Analysis of Key Immune Checkpoint Receptors on Tumor-Infiltrating T Cells From Multiple Types of Cancer

Abstract

Background: Cancer patients often display dysfunctional antitumor T-cell responses. Because noteworthy benefits of immune checkpoint pathway blockade, such as programmed cell death protein 1 (PD-1) inhibitors, have been achieved in multiple advanced cancers, the next critical question is which mono-blockade or combinatorial blockade regimens may reinvigorate antitumor T-cell immunity in those cancer patients while limiting immune-related adverse effects.Method: This study recruited, in total, 172 primary cancer patients (131 were blood-tumor-matched patients) who were treatment-naïve prior to the surgeries or biopsies covering the eight most prevalent types of cancer. With access to fresh surgical samples, this study simultaneously investigated the ex vivo expression level of eight known immune checkpoint receptors [PD-1, cytotoxic T-lymphocyte antigen-4 [CTLA-4], T-cell immunoglobulin and mucin-domain containing-3 [Tim-3], 2B4, killer cell lectin like receptor G1 [KLRG-1], TIGIT, B- and T-lymphocyte attenuator [BTLA], and CD160] on tumor-infiltrating T cells (TILs) and paired circulating T cells in blood from a 131-patient cohort.Results: We found increased an expression of PD-1 and Tim-3 but a decreased expression of BTLA on TILs when compared with peripheral blood from multiple types of cancer. Moreover, our co-expression analysis of key immune checkpoint receptors delineates “shared” subsets as PD-1+Tim-3+TIGIT+2B4+KLRG-1–CTLA-4– and PD-1+TIGIT+2B4+Tim-3–KLRG-1–CTLA-4– from bulk CD8 TILs. Furthermore, we found that a higher frequency of advanced differentiation stage T cells (CD27–CCR7–CD45RA–) among the “shared” subset (PD-1+Tim-3+TIGIT+2B4+KLRG-1–CTLA-4–) in bulk CD8 TILs was associated with poorly differentiated cancer type in cervical cancer patients.Conclusions: To our knowledge, our study is the first comprehensive analysis of key immune checkpoint receptors on T cells in treatment-naïve, primary cancer patients from the eight most prevalent types of cancer. These findings might provide useful information for future design of mono-blockade/combinatorial blockades and/or genetically modified T-cell immunotherapy.

Vaginal microbiota, genital inflammation, and neoplasia impact immune checkpoint protein profiles in the cervicovaginal microenvironment

“…We observed the complex network among immune checkpoint molecules, as many of them correlate to other immune checkpoint proteins. This can reflect previous observations that these proteins are frequently co-expressed on multiple cell types, including T cells, antigen-presenting cell, and/or malignant cells 47 . We also observed that several immune checkpoint proteins positively correlate to genital inflammation, which was highly elevated in cancer patients compared with other groups 18 .…”

Human cancer germline antigen-specific cytotoxic T cell—what can we learn from patient

“…77 A recent study in our group has shown that the expression of BTLA, TIGIT, KLRG-1, and 2B4 is not enriched on TILs compared with their counterparts in peripheral blood of cancer patients. 78 Most importantly, we found that co-expression of specific IRs including Tim3 and PD-1 is highly prevalent on CD8 + TILs across different cancer types, such as in lung, kidney, and breast cancers. This suggests that certain IRs are likely more favored in the tumor microenvironment to suppress antitumor CTLs responses.…”

Identification of prognosis-related genes in the cervical cancer immune microenvironment

“…Among them, CD27 and CCR7 were markers of T cell differentiation. Previous studies showed that advanced CD27 − CCR7 − CD45RA − T cell of PD-1 + TIGIT + 2B4 + Tim-3 + KLRG-1 − CTLA-4 − CD8 TILs was related to poorly differentiated cervical cancer (37), and CCR7 might be associated with lymph node metastasis. So that they could be used as a prognostic factor for survival (38).…”