Tumor PD-L1 expression, immune cell correlates and PD-1+ lymphocytes in sentinel lymph node melanoma metastases

Abstract

Melanoma patients with sentinel lymph node metastases have variable 5-year survival rates (39-70%). The prognostic significance of tumor-infiltrating lymphocytes in sentinel lymph node metastases from such patients is currently unknown. Anti-PD-1/PD-L1 inhibitors have significantly improved clinical outcome in unresectable AJCC stage IIIC/IV metastatic melanoma patients, and are being trialed in the adjuvant setting in advanced stage disease, however, their role in early stage (sentinel lymph node positive) metastatic disease remains unclear. The aims of this study were to characterize, in sentinel lymph nodes, the subpopulations of lymphocytes that interact with metastatic melanoma cells and analyze their associations with outcome, and to determine tumor PD-L1 expression as this may provide a rational scientific basis for the administration of adjuvant anti-PD-1/PD-L1 inhibitors in sentinel lymph node positive metastatic melanoma patients. Sentinel lymph nodes containing metastatic melanoma from 60 treatment-naive patients were analyzed for CD3, CD4, CD8, FOXP3, PD-1, and PD-L1 using immunohistochemistry on serial sections. The results were correlated with clinicopathologic features and outcome. Positive correlations between recurrence-free/overall survival with the number of CD3+ tumorinfiltrating lymphocytes (hazard ratio = 0.36 (0.17-0.76), P = 0.005; hazard ratio = 0.29 (0.14-0.61), P = 0.0005, respectively), the number of CD4+ tumor-infiltrating lymphocytes (hazard ratio = 0.34 (0.15-0.77), P = 0.007; hazard ratio = 0.32 (0.14-0.74), P = 0.005, respectively), and the number of CD8+ tumor-infiltrating lymphocytes (hazard ratio = 0.42 (0.21-0.85), P = 0.013; hazard ratio = 0.32 (0.19-0.78), P = 0.006, respectively) were observed. There was also a negative correlation with the number of peritumoral PD-1+ lymphocytes (hazard ratio = 2.67 (1.17-6.13), P = 0.016; hazard ratio = 2.74 (1.14-6.76), P = 0.019, respectively). Tumoral PD-L1 expression was present in 26 cases (43%) but did not correlate with outcome. The findings suggest that T-cell subsets in sentinel lymph node metastases can predict melanoma patient outcome. In addition, the relatively high number of PD-L1 positive sentinel lymph node melanoma metastases provides a rationale for anti-PD-1 therapy trials in sentinel lymph node positive melanoma patients, particularly those with peritumoral PD-1+ lymphocytes.

Prognostic significance of tumor-infiltrating immune cells and PD-L1 expression in esophageal squamous cell carcinoma

“…Therefore, tumor PD-L1 overexpression confers a worse prognosis across multiple tumor histologies [30]. Similar to previous studies [27, 31, 32], we choose a 1% PD-L1 cut-off in this study, and found that PD-L1+ patients who received curative esophagectomy or definitive chemo-(radiation) therapy had significantly shorter DFS and OS than PD-L1– patients, and these results provide a rationale for therapeutic intervention targeted to this immunomodulatory axis in these two groups, such as adjuvant therapy with an anti-PD-1/anti-PD-L1 antibody or concurrent anti-PD-1/anti-PD-L1 antibody and radiation treatment [33]. Neither PFS nor OS were significantly different between PD-L1+ and PD-L1– patients who received palliative chemotherapy, which might because of the wide variety of chemotherapy regimens and cycles.…”

Assessing Tumor-Infiltrating Lymphocytes in Solid Tumors: A Practical Review for Pathologists and Proposal for a Standardized Method from the International Immuno-Oncology Biomarkers Working Group: Part 2: TILs in Melanoma, Gastrointestinal Tract Carcinomas, Non–Small Cell Lung Carcinoma and Mesothelioma, Endometrial and Ovarian Carcinomas, Squamous Cell Carcinoma of the Head and Neck, Genitourinary Carcinomas, and Primary Brain Tumors

“…The lymphocytic infiltrate within the metastatic tumor nests (carefully excluding the surrounding lymphoid stroma from the assessment) was found to be an independent prognostic factor [29]. Similar results were demonstrated by Bogunovic et al [30] and Kakavand et al [31], using both H&E TIL assessment and semi-quantitative scoring of immunohistochemical stained sections. Recently, as part of The Cancer Genome Atlas project, a modified TILs scoring system was used to correlate histological assessment of TILs with RNA-based gene expression profiling and survival [32].…”

Immunomodulators targeting the PD‐1/PD‐L1 protein‐protein interaction: From antibodies to small molecules

“…PD‐1 is highly expressed on tumor‐infiltrating lymphocytes, whereas PD‐L1 and PD‐L2 are elevated on a variety of cancers, with PD‐L2 expression across tumor types being much less prevalent than PD‐L1 . The overexpression of PD‐L1 in several cancers has been correlated with poor prognosis .…”