Tumor-infiltrating mast cells are associated with resistance to anti-PD-1 therapy

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• Anti-programmed death-1 (PD-1) therapy is a cornerstone of cancer treatment, yet resistance mechanisms remain poorly understood.
• Understanding resistance is crucial for improving patient outcomes and developing more effective immunotherapies.

Purpose of the Study:

• To investigate the mechanisms of resistance to anti-PD-1 therapy in melanoma.
• To identify potential strategies for overcoming this resistance.

Main Methods:

• Generation of a humanized (Hu)-mouse melanoma model using immune-deficient NSG mice, human fetal liver cells, and autologous thymus.
• Treatment of reconstituted Hu-mice with anti-PD-1 therapy and subsequent analysis of tumor microenvironment via RNA-seq, multiplexed imaging, and immunohistology.
• Combination therapy using anti-PD-1 with sunitinib or imatinib to assess impact on tumor regression and mast cell depletion.

Main Results:

• Anti-PD-1 therapy restricted tumor growth but did not achieve complete regression in the Hu-mouse melanoma model.
• Tumor regions resistant to anti-PD-1 therapy showed high chemokine expression, recruitment of FOXP3+ regulatory T cells (Tregs) and mast cells.
• Co-localization of Tregs and mast cells was associated with reduced HLA-class I expression and impaired CD8+ T cell function, correlating with therapy resistance.
• Combination therapy with anti-PD-1 and sunitinib or imatinib led to mast cell depletion and complete tumor regression.

Conclusions:

• Mast cells play a significant role in mediating resistance to anti-PD-1 therapy in melanoma.
• Targeting mast cells, potentially through combination with agents like sunitinib or imatinib, represents a promising strategy to enhance anti-PD-1 therapy efficacy.