2. Academic Validation
  3. Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma

Combined BRAF, MEK, and CDK4/6 Inhibition Depletes Intratumoral Immune-Potentiating Myeloid Populations in Melanoma

  • Cancer Immunol Res. 2021 Feb;9(2):136-146. doi: 10.1158/2326-6066.CIR-20-0401.
Emily J Lelliott 1 2,  Stefano Mangiola 3,  Kelly M Ramsbottom 1,  Magnus Zethoven 1,  Lydia Lim 1,  Peter K H Lau 1 2,  Amanda J Oliver 1 2,  Luciano G Martelotto 4,  Laura Kirby 1,  Claire Martin 1,  Riyaben P Patel 1,  Alison Slater 1,  Carleen Cullinane 1,  Anthony T Papenfuss 1,  Nicole M Haynes 1 2,  Grant A McArthur  # 1 2,  Jane Oliaro  # 1 2 5,  Karen E Sheppard  # 6 2 7
Affiliations

Affiliations

  • 1 Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.
  • 2 Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Victoria, Australia.
  • 3 The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
  • 4 Single Cell Innovation Laboratory, The University of Melbourne, Parkville, Victoria, Australia.
  • 5 Department of Immunology, Central Clinical School, Monash University, Melbourne, Victoria, Australia.
  • 6 Cancer Research Division, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia. karen.sheppard@petermac.org.
  • 7 Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria, Australia.
  • # Contributed equally.
PMID: 33303574 DOI: 10.1158/2326-6066.CIR-20-0401
Abstract

Combined inhibition of BRaf, MEK, and CDK4/6 is currently under evaluation in clinical trials for patients with melanoma harboring a BRafV600 mutation. While this triple therapy has potent tumor-intrinsic effects, the impact of this combination on antitumor immunity remains unexplored. Here, using a syngeneic BRafV600ECdkn2a-/-PTEN-/- melanoma model, we demonstrated that triple therapy promoted durable tumor control through tumor-intrinsic mechanisms and promoted immunogenic cell death and T-cell infiltration. Despite this, tumors treated with triple therapy were unresponsive to Immune Checkpoint blockade (ICB). Flow cytometric and single-cell RNA Sequencing analyses of tumor-infiltrating immune populations revealed that triple therapy markedly depleted proinflammatory macrophages and cross-priming CD103+ dendritic cells, the absence of which correlated with poor overall survival and clinical responses to ICB in patients with melanoma. Indeed, immune populations isolated from tumors of mice treated with triple therapy failed to stimulate T-cell responses ex vivo While combined BRaf, MEK, and CDK4/6 inhibition demonstrates favorable tumor-intrinsic activity, these data suggest that collateral effects on tumor-infiltrating myeloid populations may impact antitumor immunity. These findings have important implications for the design of combination strategies and clinical trials that incorporate BRaf, MEK, and CDK4/6 inhibition with immunotherapy for the treatment of patients with melanoma.

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