1. Quantitative Spatial Profiling of PD-1/PD-L1 Interaction and HLA-DR/IDO-1 Predicts Improved Outcomes of Anti-PD-1 Therapies in Metastatic Melanoma.
- Author
-
Johnson, Douglas B, Bordeaux, Jennifer, Kim, Ju Young, Vaupel, Christine, Rimm, David L, Ho, Thai H, Joseph, Richard W, Daud, Adil I, Conry, Robert M, Gaughan, Elizabeth M, Hernandez-Aya, Leonel F, Dimou, Anastasios, Funchain, Pauline, Smithy, James, Witte, John S, McKee, Svetlana B, Ko, Jennifer, Wrangle, John M, Dabbas, Bashar, Tangri, Shabnam, Lameh, Jelveh, Hall, Jeffrey, Markowitz, Joseph, Balko, Justin M, and Dakappagari, Naveen
- Subjects
Cell Line ,Tumor ,Humans ,Melanoma ,Neoplasm Metastasis ,HLA-DR Antigens ,Biopsy ,Neoplasm Staging ,Prognosis ,Treatment Outcome ,Retreatment ,Immunohistochemistry ,Protein Binding ,Models ,Biological ,Adult ,Aged ,Middle Aged ,Female ,Male ,Indoleamine-Pyrrole 2 ,3 ,-Dioxygenase ,Programmed Cell Death 1 Receptor ,Biomarkers ,Tumor ,Antineoplastic Agents ,Immunological ,B7-H1 Antigen ,Cancer ,Prevention ,Clinical Research ,2.1 Biological and endogenous factors ,Aetiology ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Oncology and Carcinogenesis ,Oncology & Carcinogenesis - Abstract
Purpose: PD-1/L1 axis-directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti-PD-1 response.Experimental Design: Pretreatment tumor biopsies from 166 patients treated with anti-PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti-PD-1 treatment outcomes.Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti-PD-1 response (P = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; P = 0.0004) and overall survival (HR = 0.39; P = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = 0.000004). In contrast, PD-L1 expression was not predictive of survival.Conclusions: Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. Clin Cancer Res; 24(21); 5250-60. ©2018 AACR.
- Published
- 2018