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Published on: February 8, 2018
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.
Abstract:
Rapid advancements in understanding how the immune system can eliminate tumors have quickly translated into breakthroughs in developing cancer therapeutics. Immune checkpoint inhibitors (ICIs) have shown great promise in several cancers; however, resistance can affect up to two-thirds of patients receiving ICIs. A significant limitation of the effectiveness of anti-PD-1 therapy centers around the insufficient levels of immune cells needed to recognize and kill cancer cells compared to the number of suppressive immune cells within the tumor microenvironment. Determining what is required to overcome the resistance to anti-PD-1 therapy in breast cancer remains a critical need. Our data demonstrate that IL-15 complexes injected intratumorally in combination with PD-1 blockade therapy induce regression of established luminal B mammary breast tumors. We show that IL-15 alone or in combination with anti-PD-1 drives changes in gene expression of pathways associated with TCR and co-stimulatory signaling, immune cell adhesion, and migration. Furthermore, we show that intratumoral injection of IL-15 complexes traffics to the tumor-draining lymph node, as evidenced by Light sheet microscopy, and colocalizes with the anti-PD-1 monoclonal antibody. We also identify the immune signatures, localization, and distribution of immune cells in regressing and non-regressing breast tumors.
Insights
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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