PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer

Abstract

Improved understanding of expression of immune checkpoint receptors (ICR) on tumor-infiltrating lymphocytes (TIL) may facilitate more effective immunotherapy in head and neck cancer (HNC) patients. A higher frequency of PD-1+ TIL has been reported in human papillomavirus (HPV)+ HNC patients, despite the role of PD-1 in T cell exhaustion. This discordance led us to hypothesize that the extent of PD-1 expression more accurately defines T cell function and prognostic impact, since PD-1high T cells may be more exhausted than PD-1low T cells and may influence clinical outcome and response to anti-PD-1 immunotherapy. In this study, PD-1 expression was indeed upregulated on HNC patient TIL, and the frequency of these PD-1+ TIL was higher in HPV+ patients (p = 0.006), who nonetheless experienced significantly better clinical outcome. However, PD-1high CD8+ TIL were more frequent in HPV− patients and represented a more dysfunctional subset with compromised IFN-γ secretion. Moreover, HNC patients with higher frequencies of PD-1high CD8+ TIL showed significantly worse disease free survival (DFS) and higher hazard ratio for recurrence (p<0.001), while higher fractions of PD-1low T cells associated with HPV positivity and better outcome. In a murine HPV+ HNC model, anti-PD-1 mAb therapy differentially modulated PD-1high/low populations, and tumor rejection associated with loss of dysfunctional PD-1high CD8+ T cells and a significant increase in PD-1low TIL. Thus, the extent of PD-1 expression on CD8+ TIL provides a potential biomarker for anti-PD-1 based immunotherapy.

Presence of few PD‐1‐expressing tumor‐infiltrating immune cells is a potential predictor of improved response to salvage chemotherapy following nivolumab for non‐small cell lung cancer: An exploratory case series

“…PD‐1 inhibitors can activate partially exhausted cytotoxic T cells and shrink the tumors, but not deeply exhausted T cells . High PD‐1‐expressing CD8 + cells secret less cytotoxic cytokines in vitro, but nivolumab does not subsequently restore the release of cytokines . Although a subset of effector T cells differentiated into effector memory T cells for durable effects of PD‐1 inhibitors, the deeply exhausted T cells were not able to differentiate into effector memory T cells .…”

Pulmonary pleomorphic carcinoma with few PD‐1‐positive immune cells and regulatory T cells that showed a complete response to nivolumab

“…However, a recent exploratory study reported an 86% response rate to nivolumab in selected lung cancer patients with tumor cells overexpressing PD‐L1 + and low levels of PD‐1 + tumor‐infiltrating lymphocytes . In a mouse cancer model, the antitumor activity of an anti‐PD‐1 antibody was associated with an increase in intratumoral CD8 + cells weakly positive for PD‐1 . Several in vitro studies using flow cytometry have shown that CD8 + cells that highly express PD‐1 release less cytokines and display less cytotoxic activity than cells that weakly express PD‐1 .…”

“…10 In a mouse cancer model, the antitumor activity of an anti-PD-1 antibody was associated with an increase in intratumoral CD8 + cells weakly positive for PD-1. 11 Several in vitro studies using flow cytometry have shown that CD8 + cells that highly express PD-1 release less cytokines and display less cytotoxic activity than cells that weakly express PD-1. 11,12 Nivolumab restores the release of cytokines in CD8 + cells that are weakly positive for PD-1, but not in cells that are highly positive for PD-1.…”

“…11 Several in vitro studies using flow cytometry have shown that CD8 + cells that highly express PD-1 release less cytokines and display less cytotoxic activity than cells that weakly express PD-1. 11,12 Nivolumab restores the release of cytokines in CD8 + cells that are weakly positive for PD-1, but not in cells that are highly positive for PD-1. 13 High levels of PD-1 expressing CD8 + cells are considered irreversibly dysfunctional, even when exposed to PD-1 inhibitor therapy.…”

Immune Checkpoint Inhibitors in Triple Negative Breast Cancer: What is the Evidence?

“…The overall survival (OS) of TNBC with rich TILs compared to TNBC with low TILs following adjuvant anthracycline was 89% and 68%, respectively [25]. Some studies did not demonstrate a positive correlation between the presence of TILs and favorable prognoses [26][27][28]. One explanation for this contradiction could be a temporal evolution of TILs, initially involved in rigorous tumor attack and later in the process expire and fatigue.…”