Myeloid cells that impair immunotherapy are restored in melanomas with acquired resistance to BRAF inhibitors

Shannon M. Steinberg, Tamer B. Shabaneh, Peisheng Zhang, Viktor Martyanov, Zhenghui Li, Brian T. Malik, Tamara A. Wood, Andrea Boni, Aleksey Molodtsov, Christina V. Angeles, Tyler J. Curiel, Michael L. Whitfield, Mary Jo Turk

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Acquired resistance to BRAFV600E inhibitors (BRAFi) in melanoma remains a common clinical obstacle, as is the case for any targeted drug therapy that can be developed given the plastic nature of cancers. Although there has been significant focus on the cancer cell-intrinsic properties of BRAFi resistance, the impact of BRAFi resistance on host immunity has not been explored. Here we provide preclinical evidence that resistance to BRAFi in an autochthonous mouse model of melanoma is associated with restoration of myeloid-derived suppressor cells (MDSC) in the tumor microenvironment, initially reduced by BRAFi treatment. In contrast to restoration of MDSCs, levels of T regulatory cells remained reduced in BRAFi-resistant tumors. Accordingly, tumor gene expression signatures specific for myeloid cell chemotaxis and homeostasis reappeared in BRAFi-resistant tumors. Notably, MDSC restoration relied upon MAPK pathway reactivation and downstream production of the myeloid attractant CCL2 in BRAFi-resistant melanoma cells. Strikingly, although combination checkpoint blockade (anti-CTLA-4 + anti-PD-1) was ineffective against BRAFi-resistant melanomas, the addition of MDSC depletion/ blockade (anti-Gr-1 + CCR2 antagonist) prevented outgrowth of BRAFi-resistant tumors. Our results illustrate how extrinsic pathways of immunosuppression elaborated by melanoma cells dominate the tumor microenvironment and highlight the need to target extrinsic as well as intrinsic mechanisms of drug resistance.

Original languageEnglish (US)
Pages (from-to)1599-1610
Number of pages12
JournalCancer Research
Volume77
Issue number7
DOIs
StatePublished - 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Myeloid cells that impair immunotherapy are restored in melanomas with acquired resistance to BRAF inhibitors'. Together they form a unique fingerprint.

Cite this