Targeted Therapy Given after Anti-PD-1 Leads to Prolonged Responses in Mouse Melanoma Models through Sustained...

Area of Science:

• Immunology and Cancer Biology
• Melanoma Therapeutics

Background:

• Immunotherapy (IT) and targeted therapy (TT) are effective melanoma treatments.
• Combining IT and TT often leads to significant toxicity.
• The optimal sequencing of IT and TT for melanoma remains under investigation.

Purpose of the Study:

• To investigate the efficacy of a sequential treatment of IT followed by TT.
• To evaluate the impact of IT→TT sequencing on antitumor responses in BRAF- and NRAS-mutant melanoma mouse models.
• To analyze the immunological and transcriptional changes induced by the IT→TT sequence.

Main Methods:

• Treatment of NRAS-mutant (SW1) and BRAF-mutant (SM1) melanoma mouse models with IT, TT, or IT→TT sequence.
• Tumor volume measurement.
• Immune-cell analysis, single-cell RNA sequencing (scRNA-seq), and reverse phase protein analysis (RPPA) of tumor samples.

Main Results:

• The IT→TT sequence significantly improved antitumor responses compared to IT or TT alone.
• scRNA-seq revealed that IT→TT modulated the immune microenvironment, increasing beneficial immune cells and decreasing suppressive ones.
• Durable responses were dependent on CD8+ T-cell activity, and the sequence promoted melanoma cell expression of MHC class I and antigens, while suppressing tumor-intrinsic signaling.

Conclusions:

• Upfront immunotherapy (IT) enhances the efficacy of subsequent targeted therapy (TT) in BRAF- and NRAS-mutant melanoma.
• The IT→TT sequence induces a favorable immune microenvironment and promotes T-cell-mediated antitumor activity.
• This sequential approach offers a promising strategy to overcome therapeutic resistance in melanoma.