Harnessing Inflammatory Monocytes to Overcome Resistance to Anti-PD-1 Immunotherapy

Area of Science:

• Immunology
• Oncology
• Cancer Research

Background:

• Immune checkpoint inhibitors (ICIs) are limited by acquired resistance in over 50% of melanoma patients.
• Somatic mutations, like beta-2 microglobulin (B2m) loss, cause tumors to evade T cell-mediated killing, leading to resistance.
• Understanding resistance mechanisms is crucial for developing effective cancer immunotherapies.

Purpose of the Study:

• To investigate mechanisms of acquired resistance to ICIs in antigen presentation-deficient tumors.
• To explore therapeutic strategies for overcoming resistance by targeting myeloid cell repolarization.
• To define the role of immune cells and cytokines in response to CD40 agonist therapy.

Main Methods:

• Single-cell RNA-seq, flow cytometry, and ex vivo assays characterized immune cells in B2m-null tumors.
• Mice with B2m-null tumors were treated with anti-PD-1 or CD40 agonist antibodies, along with cell depletion or cytokine blockers.
• Published human RNA-seq datasets were analyzed to assess inflammatory monocyte contributions to patient outcomes.

Main Results:

• B2m-null tumors showed increased immunosuppressive macrophages; CD40 agonist treatment reduced tumor growth and improved survival.
• CD40 agonist efficacy required CD8+ T cells and NK cells, which mediated tumor control via IFNγ secretion, not direct tumor cell recognition.
• IFNγ receptor expression on host cells, not tumor cells, was essential for CD40 agonist efficacy.
• A distinct inflammatory monocyte population with an IFNγ response signature was identified in treated tumors.
• Analysis of human datasets linked an inflammatory monocyte signature to improved patient outcomes and ICI response.

Conclusions:

• CD8+ T cells can control tumor growth even without direct tumor antigen presentation.
• Activating inflammatory monocyte effector functions represents a potential strategy to overcome ICI resistance.
• Targeting myeloid cell repolarization may enhance anti-tumor immunity and improve therapeutic responses.