title: 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+ tumor-infiltrating 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.
authors.affiliation: Melanoma Institute Australia, North Sydney, NSW, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Hojabr
authors.initials: H
authors.lastname: Kakavand
authors.affiliation: Melanoma Institute Australia, North Sydney, NSW, Australia.|Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: Ricardo E
authors.initials: RE
authors.lastname: Vilain
authors.affiliation: Melanoma Institute Australia, North Sydney, NSW, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: James S
authors.initials: JS
authors.lastname: Wilmott
authors.affiliation: Melanoma Institute Australia, North Sydney, NSW, Australia.
authors.forename: Hazel
authors.initials: H
authors.lastname: Burke
authors.affiliation: Merck Research Laboratories, Palo Alto, CA, USA.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Yearley
authors.affiliation: Melanoma Institute Australia, North Sydney, NSW, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: John F
authors.initials: JF
authors.lastname: Thompson
authors.affiliation: Melanoma Institute Australia, North Sydney, NSW, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.|Kolling Institute of Medical Research, Royal North Shore Hospital, St. Leonards, NSW, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Hersey
authors.affiliation: Melanoma Institute Australia, North Sydney, NSW, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.
authors.forename: Georgina V
authors.initials: GV
authors.lastname: Long
authors.affiliation: Melanoma Institute Australia, North Sydney, NSW, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.|Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, NSW, Australia.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Scolyer
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D060890:B7-H1 Antigen / Q000032:analysis / Q000096:biosynthesis*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000276:immunology; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis / Q000276:immunology* / Q000473:pathology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor / Q000032:analysis / Q000096:biosynthesis; D016016:Proportional Hazards Models; D021701:Sentinel Lymph Node Biopsy; D012878:Skin Neoplasms / Q000276:immunology* / Q000401:mortality / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000276:immunology*; D055815:Young Adult
chemical_list: D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor