2. Academic Validation
  3. RAS/MEK/PI3K pathway inhibition augments response to CD40 agonism by targeting CD11b+ Bregs thereby overcoming melanoma PD1-resistance

RAS/MEK/PI3K pathway inhibition augments response to CD40 agonism by targeting CD11b+ Bregs thereby overcoming melanoma PD1-resistance

  • Nat Commun. 2026 Jan 12;17(1):162. doi: 10.1038/s41467-025-67315-1.
Chi Yan 1 2 3 4,  Weifeng Luo 5 6,  Jinming Yang 5 6,  Jing Yang 7 8,  Sheau-Chiann Chen 7,  Kensey Bergdorf 5 6,  Qianni Hu 9,  Vivian L Weiss 10,  Douglas B Johnson 9,  Qi Liu 7 8,  Ann Richmond 11 12
Affiliations

Affiliations

  • 1 Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA. [email protected].
  • 2 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA. [email protected].
  • 3 Department of Immunology, Max Rady College of Medicine and Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada. [email protected].
  • 4 Paul Albrechtsen Research Institute, CancerCare Manitoba, Winnipeg, MB, Canada. [email protected].
  • 5 Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.
  • 6 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 7 Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN, USA.
  • 8 Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 9 Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 10 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 11 Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA. [email protected].
  • 12 Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA. [email protected].
PMID: 41526341 DOI: 10.1038/s41467-025-67315-1
Abstract

Development of effective second-line treatment options for patients with BRAFwtNRASwt or BRAFwtNRASmut melanoma resistant to immune checkpoint blockade (ICB) is crucial. While systemic delivery of agonist CD40 (aCD40) plus anti-PD1 (αPD1) showed activity in patients with ICB-resistant melanoma, the objective response rate was modest (15%), in part due to induction of B regulatory cells (Bregs) which suppress CD8+ effector T cell responses. We previously reported that Ras/Raf/PI3K-inhibition elevates CD40 expression in melanoma cells and sensitizes tumors to ICB. Here, we show that combined treatment with a Ras/PI3K/AKT-pathway inhibitor rigosertib (RGS), and/or a MEK1/2 inhibitor trametinib (T), plus aCD40, overcomes the ICB resistance of BRAFwtNRASwt and BRAFwtNRASmut melanoma tumors growing in C57BL/6 mice. In addition, overexpression of CD40 in these melanoma cells effectively reverses ICB-resistance and aCD40 + αPD1 treatment induces tumor regression. Mechanistically, RGS + T suppress aCD40-associated CD11b+PD-L1+ Bregs, promoting CD8+ T-cell mediated killing in melanoma. scRNA-Seq analyses confirm CD40-associated CD11b+ Bregs across Cancer types in patients. Our data demonstrate that addition of Ras/PI3K/Akt and MEK inhibitors to aCD40 resolves the issue of aCD40 induction of CD11b+PD-L1+ Bregs and provides alternative therapeutic options for ICB-resistant BRAFwtNRASwt or BRAFwtNRASmut metastatic melanoma.

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