Chemotherapeutic Treatments Increase PD-L1 Expression in Esophageal Squamous Cell Carcinoma through EGFR/ERK Activation

Abstract

The current study reveals the clinicopathological association of PD-L1 in Hong Kong esophageal squamous cell carcinoma (ESCC) patients and the differential regulation of PD-L1 by standard first-line chemotherapy in ESCC. Immunohistochemical analysis of tissue microarray data from 84 Hong Kong ESCC patients shows that PD-L1 was expressed in 21% of the tumors. Positive PD-L1 staining was significantly associated with later disease stage (stages III and IV) (P value = .0379) and lymph node metastasis (P value = .0466) in the Hong Kong cohort. Furthermore, PD-L1 expression was significantly induced in ESCC cell lines after standard chemotherapy treatments, along with EGFR and ERK activation in both in vitro studies and the in vivo esophageal orthotopic model. The endogenous expression of PD-L1 was reduced by treatment with an EGFR inhibitor (erlotinib) or by the knockdown of EGFR. Moreover, the upregulation of PD-L1 by chemotherapy was also attenuated by the treatment with erlotinib and a MAPK/MEK inhibitor (AZD6244), suggesting that PD-L1 is regulated by the EGFR/ERK pathway in ESCC. The regulation of PD-L1 by the EGFR pathway was further supported by the correlation of PD-L1 and EGFR expression observed in the commercially available tissue microarray set (P value = .028). Taken together, the current study was the first to demonstrate the upregulation of PD-L1 by chemotherapy in ESCC and its regulation through the EGFR/ERK pathway. The results suggest the potential usefulness of combined conventional chemotherapy together with anti–PD-L1 immunotherapy to achieve better treatment outcome.

Programmed Cell Death Ligand 1 in Breast Cancer: Technical Aspects, Prognostic Implications, and Predictive Value

“…In particular, it has recently been shown that PD‐L1 significantly increased on residual disease after NACT compared with baseline in a large retrospective cohort of patients with TN early BC . The induction of PD‐L1 expression by chemotherapy is consistent with observations in other cancer types and with the notion that chemotherapy is able to induce an adaptive immune response through various mechanisms, including immunogenic cell death and the activation of the damage response c‐GAS/STING . Indeed, it has been shown that CT may boost the immunogenicity of the tumor by increasing tumor immune infiltrate from baseline to post‐NACT samples, with a high rate of conversion from low‐TIL to high‐TILs tumor .…”

Therapeutic cooperation between auranofin, a thioredoxin reductase inhibitor and anti‐PD‐L1 antibody for treatment of triple‐negative breast cancer

“…Moreover, at the end of a 2‐week treatment cycle, we observed that 4T1.2 and MDA‐MB‐231 tumors regained growth, suggesting the presence of a resistance mechanism against AF. In recent years, upregulation of immune checkpoint PD‐L1 has emerged as a potential resistance mechanism to neoadjuvant chemotherapies and targeted therapies . TNBC patients with high PD‐L1 expression on tumor cells have extremely unfavorable outcomes after chemotherapy compared to patients with low PD‐L1 expression .…”

“…In recent years, upregulation of immune checkpoint PD-L1 has emerged as a potential resistance mechanism to neoadjuvant chemotherapies and targeted therapies. 17,35 TNBC patients with high PD-L1 expression on tumor cells have extremely unfavorable outcomes after chemotherapy compared to patients with low PD-L1 expression. 40 Based on this data, it may imply that PD-L1 upregulation may lead to AF resistance in TNBCs.…”

“…PD‐L1 is overexpressed in approximately 20–30% of TNBC patients and is associated with poor prognosis . Increased PD‐L1 expression in response to chemotherapy and targeted therapies leads to drug resistance in multiple cancers . Hence, combining immunotherapy targeting the PD‐1/PD‐L1 axis with conventional chemotherapy and targeted therapy represents an effective approach for cancer treatment.…”

PD‐L1 expression, CD8+ and CD4+ lymphocyte rate are predictive of pathological complete response after neoadjuvant chemoradiotherapy for squamous cell cancer of the thoracic esophagus

“…PD‐L1 expression was assessed both in neoplastic epithelia and in infiltrating leukocytes. Three different parameters were considered: (a) PD‐L1 staining intensity in neoplastic cells categorizing cases in high (in presence of staining detected up to 5% of the neoplastic cells) and low (<5%) PD‐L1 expression; (b) a semiquantitative pathology H‐score, defined as the aggregate of total percentage of tumor cells expressing PD‐L1 at each particular intensity level from 0, +1 (weak intensity), +2 (moderate intensity) or +3 (strong intensity); in brief, the H score was defined as (Percent of PD‐L1 1+ tumor cells multiplied by intensity of 1) + (Percent of PD‐L1 2+ tumor cells multiplied by intensity of 2) + (Percent of PD‐L1 3+ tumor cells multiplied by intensity of 3), and this composite score can range from 0 (a tumor which is completely negative) to a maximum of 300 (a tumor in which all the cells feature a 3+ staining); (c) stromal positive leukocytes were counted in 5 HPF (40×) …”