Anti-PD-1/L1 lead-in before MAPK inhibitor combination maximizes antitumor immunity and efficacy

Cancer Cell. 2021 Oct 11;39(10):1375-1387.e6. doi: 10.1016/j.ccell.2021.07.023. Epub 2021 Aug 19.


Rationally sequencing and combining PD-1/L1-and MAPK-targeted therapies may overcome innate and acquired resistance. Since increased clinical benefit of MAPK inhibitors (MAPKi) is associated with previous immune checkpoint therapy, we compare the efficacies of sequential and/or combinatorial regimens in subcutaneous murine models of melanoma driven by BrafV600, Nras, or Nf1 mutations as well as colorectal and pancreatic carcinoma driven by KrasG12C. Anti-PD-1/L1 lead-in preceding MAPKi combination optimizes response durability by promoting pro-inflammatory polarization of macrophages and clonal expansion of interferon-γhi, and CD8+ cytotoxic and proliferative (versus CD4+ regulatory) T cells that highly express activation genes. Since therapeutic resistance of melanoma brain metastasis (MBM) limits patient survival, we demonstrate that sequencing anti-PD-1/L1 therapy before MAPKi combination suppresses MBM and improves mouse survival with robust T cell clonal expansion in both intracranial and extracranial metastatic sites. We propose clinically testing brief anti-PD-1/L1 (± anti-CTLA-4) dosing before MAPKi co-treatment to suppress therapeutic resistance.

Trial registration: NCT02196181.

Keywords: BRAF/NRAS/KRAS/NF1; MAPK/BRAF/MEK inhibitor resistance; anti-CTLA-4; anti-PD-1/L1; brain metastasis; colorectal carcinoma; melanoma; pancreatic ductal adenocarcinoma; sequential-combination therapy; tumor immune microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use*
  • Immunotherapy / methods*
  • Mice
  • Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors*
  • Neoplasms / drug therapy*


  • Immune Checkpoint Inhibitors
  • Mitogen-Activated Protein Kinase Kinases

Associated data