Programmed death-ligand 1 expression correlates with diminished CD8+ T cell infiltration and predicts poor prognosis in anal squamous cell carcinoma patients

Abstract

ObjectiveIncreased expression of programmed death-ligand 1 (PD-L1) on tumor cells can be found in various malignancies; however, very limited information is known about its role in anal squamous cell carcinoma (ASCC). This study explored PD-L1 expression in ASCC patients and its association with patients’ clinicopathological features, CD8+ T cell infiltration, and prognosis.MethodsFormalin-fixed paraffin-embedded tumor samples from 26 patients with ASCC were retrieved. The levels of PD-L1 expression on the membrane of both tumor cells and tumor-infiltrating mononuclear cells (TIMCs) were evaluated by immunohistochemistry. CD8+ T cell densities, both within tumors and at the tumor–stromal interface, were also analyzed. Baseline clinicopathological characteristics, human papilloma virus (HPV) status, and outcome data correlated with PD-L1-positive staining.ResultsPD-L1 expression on tumor cells and TIMCs was observed in 46% and 50% of patients, respectively. Nineteen patients (73%) were HPV positive, with 7 showing PD-L1-positive staining on tumor cells and 9 showing PD-L1-positive staining on TIMCs. Increasing CD8+ density within tumors, but not immune stroma, was significantly associated with decreased PD-L1 expression by both tumor cells and TIMCs (P=0.0043 and P=0.0007). Patients with negative PD-L1 expression had significantly better progression-free survival (P=0.038 and P=0.0443) and a non-statistically significant trend toward longer overall survival (P=0.0882 and P=0.1222) compared with patients with positive PD-L1 expression.ConclusionPD-L1 is widely expressed on the membrane of tumor cells and TIMCs in ASCCs. Its negative impact on prognosis may be due to the diminished CD8+ T cell infiltration within tumors.

Evaluation of PD-L1 Expression and HPV Genotyping in Anal Squamous Cell Carcinoma

“…For example, NSCLC and melanoma patients with PD-L1-expressing tumors responded better to ICB targeting the PD-1/PD-L1 axis [15]. A subgroup of anal cancer patients expressed PD-L1 on the tumor cells, as reported in previous reports [20][21][22] and, interestingly, this was also the case in almost two-thirds of the patients in our study population, indicating that these tumors might be susceptible to ICB. Furthermore, most of the anal cancer patients were infected with HPV.…”

PD-1/PD-L1 expression in anal squamous intraepithelial lesions

“…This recruitment may have a role in viral clearance in regressing cervical intra epithelial lesion [17]. Furthermore, a decreased number of CD8+ lymphocytes and their association with PD-L1 expression in tumor cells has also been described in anal squamous cell carcinoma [9], suggesting that activation of PD-L1 pathway may induce a immune tolerant profile accelerating immune escapement of tumor cells.…”

“…described that a high amount of PD-1 positive tumor infiltrating lymphocytes was associated with better disease-free survival. In contrast, others found that PD-L1 expression was associated with a worse prognosis [9,10]. Immune checkpoint inhibition has only been reported in a limited series of patients with locally advanced, recurrent or metastatic ASCC, showing 24% of tumor response [11].…”

High IDO1 Expression Is Associated with Poor Outcome in Patients with Anal Cancer Treated with Definitive Chemoradiotherapy

“…One study showed that tumors with high PD-1 (in addition to high CD8+ TIL) had better local control and disease-free survival, with high PD-L1 specifically correlated with better local control [18]. However, a different group has shown presence of PD-L1 on tumor cells to be inversely correlated with CD8+ TIL such that high PD-L1 is negatively prognostic in terms of response to standard therapy [19]. Although our results did not show these markers to be individually prognostic, it is interesting that IDO1 was robustly associated with poor outcome and was associated with the lowest quartile of CD8+ TIL, which fits in the general paradigm of low TIL being negatively prognostic.…”