Recurrent tumor cell–intrinsic and –extrinsic alterations during mapki-induced melanoma regression and early adaptation

Chunying Song, Marco Piva, Lu Sun, Aayoung Hong, Gatien Moriceau, Xiangju Kong, Hong Zhang, Shirley Lomeli, Jin Qian, Clarissa C. Yu, Robert Damoiseaux, Mark C. Kelley, Kimberley B. Dahlman, Philip O. Scumpia, Jeffrey A. Sosman, Douglas B. Johnson, Antoni Ribas, Willy Hugo, Roger S. Lo*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

66 Scopus citations

Abstract

Treatment of advanced BRAFV600-mutant melanoma using a BRAF inhibitor or its combination with a MEK inhibitor typically elicits partial responses. We compared the transcriptomes of patient-derived tumors regressing on MAPK inhibitor (MAPKi) therapy against MAPKi-induced temporal transcriptomic states in human melanoma cell lines or murine melanoma in immune-competent mice. Despite heterogeneous dynamics of clinical tumor regression, residual tumors displayed highly recurrent transcriptomic alterations and enriched processes, which were also observed in MAPKi-selected cell lines (implying tumor cell–intrinsic reprogramming) or in bulk mouse tumors (and the CD45-negative or CD45-positive fractions, implying tumor cell–intrinsic or stromal/ immune alterations, respectively). Tumor cell–intrinsic reprogramming attenuated MAPK dependency, while enhancing mesenchymal, angiogenic, and IFN-inflammatory features and growth/survival dependence on multi-RTKs and PD-L2. In the immune compartment, PD-L2 upregulation in CD11c+ immunocytes drove the loss of T-cell inflammation and promoted BRAFi resistance. Thus, residual melanoma early on MAPKi therapy already displays potentially exploitable adaptive transcriptomic, epigenomic, immune-regulomic alterations. SIGNIFICANCE: Incomplete MAPKi-induced melanoma regression results in transcriptome/methylome-wide reprogramming and MAPK-redundant escape. Although regressing/residual melanoma is highly T cell–inflamed, stromal adaptations, many of which are tumor cell–driven, could suppress/eliminate intratumoral T cells, reversing tumor regression. This catalog of recurrent alterations helps identify adaptations such as PD-L2 operative tumor cell intrinsically and/or extrinsically early on therapy.

Original languageEnglish (US)
Pages (from-to)1248-1265
Number of pages18
JournalCancer discovery
Volume7
Issue number11
DOIs
StatePublished - Nov 2017

ASJC Scopus subject areas

  • Oncology

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