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IL-15 Complexes Combined with PD-1 Blockade Affect Immune Cell Distribution, Localization, and Immune Signatures in
Josef W Goldufsky1, Anjelica F Reyes2, Allie A Heller1,2
1Department of Internal Medicine, Division of Hematology and Oncology, Rush University Medical Center, Chicago, IL 60612, USA.
International Journal of Molecular Sciences
|December 11, 2025
Summary
Combining IL-15 complexes with PD-1 blockade therapy can overcome resistance to cancer immunotherapy. This approach promotes immune cell activity and tumor regression in breast cancer models.
Area of Science:
- Oncology
- Immunology
- Cancer Therapeutics
Background:
- Immune checkpoint inhibitors (ICIs) like anti-PD-1 therapy show promise but face resistance in many cancers.
- Resistance to anti-PD-1 therapy is often linked to insufficient anti-tumor immune cells and a suppressive tumor microenvironment.
- Overcoming anti-PD-1 resistance in breast cancer requires understanding immune cell dynamics and enhancing anti-tumor immunity.
Purpose of the Study:
- To investigate the efficacy of intratumoral IL-15 complexes combined with PD-1 blockade in overcoming breast cancer resistance.
- To elucidate the immunological mechanisms underlying tumor regression induced by this combination therapy.
- To identify immune signatures associated with response and non-response to combined therapy.
Main Methods:
- Intratumoral injection of IL-15 complexes and anti-PD-1 monoclonal antibody in a luminal B mammary breast tumor model.
- Gene expression analysis to identify changes in immune-related pathways.
- Light sheet microscopy to track IL-15 complex trafficking and colocalization with anti-PD-1.
- Analysis of immune cell signatures, localization, and distribution in tumors.
Main Results:
- Intratumoral IL-15 complexes plus PD-1 blockade induced regression of established breast tumors.
- This combination therapy altered gene expression, enhancing TCR and co-stimulatory signaling, and promoting immune cell adhesion and migration.
- IL-15 complexes were observed to traffic to tumor-draining lymph nodes and colocalize with anti-PD-1.
- Distinct immune signatures were identified in regressing versus non-regressing tumors.
Conclusions:
- Intratumoral IL-15 complexes combined with PD-1 blockade represent a potential strategy to overcome resistance to anti-PD-1 therapy in breast cancer.
- The combination therapy enhances anti-tumor immunity by modulating immune cell signaling, trafficking, and infiltration.
- Understanding immune cell dynamics is crucial for developing effective cancer immunotherapies and predicting treatment response.
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