RAS/MEK/PI3K pathway inhibition augments response to CD40 agonism by targeting CD11b⁺ Bregs thereby overcoming...

Area of Science:

• Oncology
• Immunology
• Molecular Biology

Background:

• Developing effective second-line treatments for BRAF wild-type (BRAF^wt) and NRAS wild-type (NRAS^wt) or mutant (NRAS^mut) melanoma resistant to immune checkpoint blockade (ICB) is critical.
• Systemic agonist CD40 (aCD40) plus anti-PD1 (αPD1) therapy showed modest activity (15% objective response rate) in ICB-resistant melanoma, partly due to induced B regulatory cells (Bregs) that suppress CD8+ T cell responses.

Purpose of the Study:

• To investigate novel therapeutic strategies to overcome ICB resistance in BRAF^wtNRAS^wt and BRAF^wtNRAS^mut melanoma.
• To evaluate the efficacy of combining RAS/PI3K/AKT and MEK inhibitors with aCD40 and αPD1 therapy.

Main Methods:

• Treatment of BRAF^wtNRAS^wt and BRAF^wtNRAS^mut melanoma tumor models in mice with rigosertib (RGS) and/or trametinib (T) plus aCD40.
• Overexpression of CD40 in melanoma cells.
• Analysis of Bregs and CD8+ T cell responses.
• Single-cell RNA sequencing (scRNA-Seq) to analyze Bregs in patient cancer types.

Main Results:

• Combined RGS and/or T with aCD40 treatment overcame ICB resistance in mouse models of BRAF^wtNRAS^wt and BRAF^wtNRAS^mut melanoma.
• Overexpression of CD40 reversed ICB resistance and induced tumor regression with aCD40 + αPD1 treatment.
• RGS + T suppressed aCD40-induced CD11b+PD-L1+ Bregs, enhancing CD8+ T cell-mediated killing.
• scRNA-Seq confirmed CD40-associated CD11b+ Bregs in human cancers.

Conclusions:

• Addition of RAS/PI3K/AKT and MEK inhibitors to aCD40 therapy resolves the issue of aCD40-induced Bregs.
• This combination strategy offers alternative therapeutic options for ICB-resistant BRAF^wtNRAS^wt or BRAF^wtNRAS^mut metastatic melanoma.