Figure S1 from BRAF and MEK Inhibitors Increase PD-1-Positive Melanoma Cells Leading to a Potential Lymphocyte-Independent Synergism with Anti–PD-1 Antibody

https://doi.org/10.1158/1078-0432.22465409

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posted on 2023-03-31, 19:51 authored by Martina Sanlorenzo, Igor Vujic, Arianna Floris, Mauro Novelli, Loretta Gammaitoni, Lidia Giraudo, Marco Macagno, Valeria Leuci, Ramona Rotolo, Chiara Donini, Marco Basiricò, Pietro Quaglino, Maria Teresa Fierro, Silvia Giordano, Maria Sibilia, Fabrizio Carnevale-Schianca, Massimo Aglietta, Dario Sangiolo

<p>Fig. S1. PD1 expression on melanoma correlates with PDL1 and PDL2. Scatter plots depicturing the correlation between (A) PD1 and PDL1, (B) PD1 and PDL2, (C) PDL1 and PDL2 in the 214 melanoma samples analyzed from the TCGA.</p>

Funding

FPRC ONLUS 5 × 1000

Associazione Italiana Ricerca sul Cancro

Ricerca Finalizzata-Giovani Ricercatori Ministero della Salute

University of Torino Fondo Ricerca Locale 2013

History

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DOI - Is supplement to BRAF and MEK Inhibitors Increase PD-1-Positive Melanoma Cells Leading to a Potential Lymphocyte-Independent Synergism with Anti–PD-1 Antibody

ARTICLE 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-1+ 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 = 61; validation cell lines, N = 7) and melanoma tumors (TCGA, N = 214). We explored in vitro how BRAF/MEKi affect rates of PD-1+, PD-L1/2+ melanoma cells, and characterized the proliferative and putative stemness features of PD-1+ 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-1+ cells increase to relevant rates during BRAF/MEKi treatment [7.3% (5.6–14.2) vs. 1.5% (0.7–3.2), P = 0.0156; N = 7], together with PD-L2+ melanoma cells [8.5% (0.0–63.0) vs. 1.5% (0.2–43.3), P = 0.0312; N = 7]. PD-1+ cells proliferate less than PD-1− cells (avg. 65% less; t = 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-1+ melanoma cells that may sustain tumor relapse, providing a lymphocyte-independent rationale to explore combinatory strategies with anti–PD-1 antibody. Clin Cancer Res; 24(14); 3377–85. ©2018 AACR.