Novel induction of CD40 expression by tumor cells with RAS/RAF/PI3K pathway inhibition augments response to checkpoint blockade

Molecular Cancer

Sheau-Chiann Chen¹  Gregory D. Ayers¹  Douglas B. Johnson²  E. Premkumar Reddy³  Anna E. Vilgelm⁴  Rebecca L. Shattuck-Brandt⁵  Ann Richmond⁵  Chi Yan⁵  Nabil Saleh⁵  Jinming Yang⁵  Caroline A. Nebhan⁶  Joseph T. Roland⁷ 

[1] Department of Biostatistics, Vanderbilt University Medical Center, Nashville, TN, USA;Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA;Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA;Department of Pathology, The Ohio State University, Columbus, OH, USA;Department of Veterans Affairs, Tennessee Valley Healthcare System, 432 PRB, 2220 Pierce Ave, 37232, Nashville, TN, USA;Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA;Department of Veterans Affairs, Tennessee Valley Healthcare System, 432 PRB, 2220 Pierce Ave, 37232, Nashville, TN, USA;Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN, USA;Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA;Departments of Surgery and Pediatrics and the Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN, USA;

关键词: RAS/RAF/PI3K;    CD40;    Immunogenic cell death;    Immune checkpoint blockade;    Melanoma;   

DOI  :  10.1186/s12943-021-01366-y

来源: Springer

【 摘 要 】

BackgroundWhile immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy.MethodsRigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAFwt and BRAFmut melanoma and analyzed in reference to patient data.ResultsRGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8+ cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40+SOX10+ melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB.ConclusionsOur data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone.Trial registrationNCT01205815 (Sept 17, 2010).Graphical abstract

【 授权许可】

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