BRAF and MEK inhibitors increase PD-1-positive melanoma cells leading to a potential lymphocyte-independent synergism with anti–PD-1 antibody

Martina Sanlorenzo, Igor Vujic, Arianna Floris, Mauro Novelli, Loretta Gammaitoni, Lidia Giraudo, Marco Macagno, Valeria Leuci, Ramona Rotolo, Chiara Donini, Marco Basirico, Pietro Quaglino, Maria Teresa Fierro, Silvia Giordano, Maria Sibilia, Fabrizio Carnevale-Schianca, Massimo Aglietta, Dario Sangiolo

Research output: Contribution to journalArticle

Abstract

Purpose: BRAF and MEK inhibitors (BRAF/MEKi) favor melanoma-infiltrating lymphocytes, providing the rationale for current combinatorial trials with anti–PD-1 antibody. A portion of melanoma cells may express PD-1, and anti–PD-1 antibody could have a direct antitumor effect. Here, we explore whether BRAF/MEKi modulate rates of PD-1þ melanoma cells, supporting an additional—lymphocyte-independent—basis for their therapeutic combination with anti–PD-1 antibody. Experimental Design: With data mining and flow cytometry, we assessed PD-1, PD-L1/2 expression on melanoma cell lines (CCLE, N ¼ 61; validation cell lines, N ¼ 7) and melanoma tumors (TCGA, N ¼ 214). We explored in vitro how BRAF/ MEKi affect rates of PD-1þ, PD-L1/2þ melanoma cells, and characterized the proliferative and putative stemness features of PD-1þ melanoma cells. We tested the functional lymphocyte-independent effect of anti–PD-1 antibody alone and in combination with BRAF/MEKi in vitro and in an in vivo immunodeficient murine model. Results: PD-1 is consistently expressed on a small subset of melanoma cells, but PD-1þ cells increase to relevant rates during BRAF/MEKi treatment [7.3% (5.6–14.2) vs. 1.5% (0.7–3.2), P ¼ 0.0156; N ¼ 7], together with PD-L2þ melanoma cells [8.5% (0.0–63.0) vs. 1.5% (0.2–43.3), P ¼ 0.0312; N ¼ 7]. PD-1þ cells proliferate less than PD-1 cells (avg. 65% less; t ¼ 7 days) and are preferentially endowed with stemness features. In vivo, the direct anti-melanoma activity of PD-1 blockage as monotherapy was negligible, but its association with BRAF/MEKi significantly delayed the development of drug resistance and tumor relapse. Conclusions: BRAF/MEKi increase the rates of PD-1þ melanoma cells that may sustain tumor relapse, providing a lymphocyte-independent rationale to explore combinatory strategies with anti–PD-1 antibody.

Original languageEnglish
Pages (from-to)3377-3385
Number of pages9
JournalClinical Cancer Research
Volume24
Issue number14
DOIs
Publication statusPublished - Jul 15 2018

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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