Tumor cell expression of programmed cell death‐1 ligand 1 is a prognostic factor for malignant melanoma

Abstract

BACKGROUND: Melanoma tends to be refractory to various immunotherapies because of tumor-induced immunosuppression. To investigate the mechanism underlining the immunosuppression of melanoma patients, the authors focused on programmed cell death-1 (PD-1)/PD-1 ligand 1 (PD-L1) interaction between tumor cells and T cells. METHODS: Melanoma specimens were collected from 59 primary tumors, 16 lymph nodes, and 4 lesions of in-transit metastasis. Specimens stained with anti-PD-L1 monoclonal antibodies were digitalized to jpg files. To evaluate the intensity of PD-L1 expression, histograms were used, and the red density (RD) was measured. PD-1 expression on T cells was analyzed in blood samples from 10 patients who had stage IV melanoma and in 4 samples of in-transit metastases. RESULTS: Twenty-five patients comprised the ''low'' PD-L1 expression group (RD value, <90), and 34 patients comprised the ''high'' group (RD value, !90). Breslow tumor thickness in the high-expression group was significantly higher than in the low-expression group. Univariate and multivariate analyses revealed that the overall survival rate of the high-expression group was significantly lower than that of the low-expression group. In all patients with stage IV disease who were examined, both CD8-positive and CD4-positive T cells had significantly higher PD-1 expression levels in the peripheral blood. Tumor-infiltrating T cells expressed high levels of PD-1, and its expression was elevated further during the clinical course. CONCLUSIONS: The current results indicated that there is a correlation between the degree of PD-L1 expression and the vertical growth of primary tumors in melanoma. Multivariate analysis demonstrated that PD-L1 expression is an independent prognostic factor for melanoma. Cancer 2010;116:1757-66.

Targeting the PD1/PD-L1 axis in melanoma: Biological rationale, clinical challenges and opportunities

“…By multivariate analysis, immunohistochemical PD-L1 expression correlated with Breslow thickness, disease free, and overall survival [47]. PD-1 + -CD8 expression/OS (P = 0.05).…”

“…The finding that PD-L1 is commonly upregulated on many different tumor types including melanoma [47], ovarian cancer [48], lung cancer [49], clear cell renal carcinoma [50], urothelial carcinoma [51], squamous cell carcinomas of the head and neck [52,53], esophageal cancer [54], cervical cancer [55], breast carcinoma [56], pancreatic cancer [57], gastric cancer [58], Wilms tumor [59] and glioblastoma [60], and that PD-1 is expressed in TILs, has created an important rationale for mAb blockade of this pathway for cancer immunotherapy.…”

“…There are important differences in the first two above referenced studies [47,65]. PD-L1 was evaluated with different immunostaining protocols.…”

“…The most noticeable difference between the Asian melanoma patient population [47] and the cohort population evaluated by Gadiot is the tumor type. In the latter, superficial spreading and nodular melanomas were predominantly diagnosed, whereas in the cohort of Hino et al, mainly patients with acral lentiginous melanomas were included.…”

PD-L1, PD-L2 and PD-1 expression in metastatic melanoma: Correlation with tumor-infiltrating immune cells and clinical outcome

“…[29][30][31][32][33][34] Its expression in the TME may be expected to reduce function of PD-1 C T cells and to have a negative impact on prognosis. 35 On the other hand, PD-L1 expression can be induced by interferons secreted in the setting of active cellular immunity and therefore may be related to better patient prognosis. 36,37 The associations of PD-L1 expression with patient prognosis and clinical characteristics remain controversial.…”