Increased PD-1+ and TIM-3+ TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients

Abstract

Despite emerging appreciation for the important role of immune checkpoint receptors in regulating the effector functions of T cells, it is unknown whether their expression is involved in determining the clinical outcome in response to cetuximab therapy. We examined the expression patterns of immune checkpoint receptors (including PD-1, CTLA-4, and TIM-3) and cytolytic molecules (including granzyme B and perforin) of CD8+ tumor-infiltrating lymphocytes (TILs) and compared them to those of peripheral blood T lymphocytes (PBLs) in patients with head and neck cancer (HNSCC) during cetuximab therapy. The frequency of PD-1 and TIM-3 expression was significantly increased in CD8+ TILs compared to CD8+ PBLs (P = 0.008 and P = 0.02, respectively). This increased CD8+ TIL population co-expressed granzyme B/perforin and PD-1/TIM-3, which suggests a regulatory role for these immune checkpoint receptors in cetuximab-promoting cytolytic activities of CD8+ TIL. Indeed, the increased frequency of PD-1+ and TIM-3+ CD8+ TILs was inversely correlated with clinical outcome of cetuximab therapy. These findings support the use of PD-1 and TIM-3 as biomarkers to reflect immune status of CD8+ T cells in the tumor microenvironment during cetuximab therapy. Blockade of these immune checkpoint receptors might enhance cetuximab-based cancer immunotherapy to reverse CD8+ TIL dysfunction, thus potentially improving clinical outcomes of HNSCC patients.

Inhibitors of the PD-1/PD-L1 axis for the treatment of head and neck cancer: current status and future perspectives

“…PD-1/PD-L1-targeted drugs show their respective antitumor effects, but whether combined application of PD-1- and PD-L1-targeted drugs can elicit enhanced effects needs further experimental verification. Cetuximab is a monoclonal antibody of the targeted EGFR, and studies have shown that blockade of PD-1/PD-L1 signaling can improve anticancer effects 49. Hence, combined application of PD-1/PD-L1-targeted drugs and cetuximab may also have favorable clinical effects.…”

Local immune parameters as potential predictive markers in head and neck squamous cell carcinoma patients receiving induction chemotherapy and cetuximab

“…High level of PD‐1 expression was detected in HNSCC TILs, and their amount proved a favorable prognostic marker . Interestingly, cetuximab treatment increased PD‐1 expression on CD8 + TILs of HNSCC patients . The high expression of both PD‐1 and its ligand PD‐L1 in head and neck cancer provides a rationale for application of anti‐PD‐1/PD‐L1 antibody therapy in this patient group …”

“…71,72 Interestingly, cetuximab treatment increased PD-1 expression on CD8 + TILs of HNSCC patients. 73 The high expression of both PD-1 and its ligand PD-L1 in head and neck cancer provides a rationale for application of anti-PD-1/PD-L1 antibody therapy in this patient group. 70,74,75 We recognize the limitations of our study.…”

Altered expression of TIM‐3, LAG‐3, IDO, PD‐L1, and CTLA‐4 during nimotuzumab therapy correlates with responses and prognosis of oral squamous cell carcinoma patients

“…Blockade of IDO‐1 combined with checkpoint receptors has been found to induce prominent antitumor responses in various solid tumors . Previous study has reported that PD‐1 + and TIM‐3 + tumor‐infiltrating lymphocytes were increased after cetuximab therapy in HNSCC patients, and the increased frequency of PD‐1 + and TIM‐3 + TILs was inversely correlated with clinical outcome of cetuximab therapy . Gefitinib, an EGFR‐tyrosine kinase inhibitors (TKIs), could cause a substantial PD‐L1 reduction in non‐small cell lung cancer but is upregulated in the patients who are acquired resistance to it .…”

“…It has been reported that PD‐1 and/or PD‐L1 was upregulated after chemotherapy in leukemia and ovarian cancer . In head and neck cancer patients, PD‐1 + and T‐cell immunoglobulin and mucin‐domain containing‐3 (TIM‐3) + tumor‐infiltrating lymphocytes (TILs) were increased during cetuximab therapy and inversely correlates with short‐term effects . Indoleamine‐2,3‐dioxygenase (IDO) is a heme enzyme participated in tryptophan catabolism and presents an immunosuppressive effect by inhibiting immune cells in tumor microenvironment .…”