Regression-Associated Macrophages Recruit Natural Killer Cells that Constrain Targeted Therapy Resistance

Area of Science:

• Immunology
• Oncology
• Cancer Therapy

Background:

• Targeted kinase inhibitors cause tumor regression but face challenges with drug-tolerant residual disease and resistance.
• While tumor-intrinsic and adaptive immunity are studied, the role of innate immunity in targeted therapy durability remains unclear.
• Understanding innate immune contributions is crucial for developing effective, long-lasting cancer treatments.

Purpose of the Study:

• To investigate the role of innate immunity, specifically natural killer (NK) cells and macrophages, in the durability of targeted cancer therapy.
• To identify mechanisms by which innate immune cells influence the development of resistance to targeted therapies.
• To explore therapeutic strategies targeting innate immunity to overcome resistance and prolong treatment response.

Main Methods:

• Utilized immunocompetent melanoma models reflecting patient treatment responses.
• Characterized immune cell infiltration, particularly NK cells and macrophages, during tumor regression and resistance phases.
• Employed genetic depletion of macrophages (LysM-cre;iDTR mice) and pharmacologic inhibition of PTPN22.
• Analyzed patient tumor datasets from melanoma and lung cancer to correlate NK cell dynamics with clinical outcomes.

Main Results:

• NK cells were found to constrain targeted therapy resistance, with infiltration peaking during regression and transitioning to an excluded state before resistance.
• A specific subset of regression-associated macrophages (F4/80hiCCL5⁺MHCII⁺CD63⁺) was identified, promoting NK cell recruitment via CCR2/5 signaling.
• Macrophage depletion impaired NK cell infiltration, while PTPN22 inhibition restored NK cell recruitment and delayed resistance onset.
• Concordant NK cell dynamics were observed in patient tumor datasets, linking innate immune responses to clinical outcomes in melanoma and lung cancer.

Conclusions:

• Innate immune remodeling, particularly NK cell recruitment orchestrated by specific macrophages, is a critical factor in the durability of targeted cancer therapy.
• Targeting NK cell recruitment represents a promising therapeutic strategy to enhance treatment response duration in oncogene-driven cancers.
• Pharmacologic modulation of immune regulators like PTPN22 can restore anti-tumor immunity and overcome therapy resistance.