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IAP Antagonists Enhance Cytokine Production from Mouse and Human iNKT Cells
Eleanor Clancy-Thompson1, Lestat Ali1, Patrick T Bruck1
1Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Abstract:
Inhibitor of apoptosis protein (IAP) antagonists are in clinical trials for a variety of cancers, and mouse models show synergism between IAP antagonists and anti-PD-1 immunotherapy. Although IAP antagonists affect the intrinsic signaling of tumor cells, their most pronounced effects are on immune cells and the generation of antitumor immunity. Here, we examined the effects of IAP antagonism on T-cell development using mouse fetal thymic organ culture and observed a selective loss of iNKT cells, an effector cell type of potential importance for cancer immunotherapy. Thymic iNKT-cell development probably failed due to increased strength of TCR signal leading to negative selection, given that mature iNKT cells treated with IAP antagonists were not depleted, but had enhanced cytokine production in both mouse and human ex vivo cultures. Consistent with this, mature mouse primary iNKT cells and iNKT hybridomas increased production of effector cytokines in the presence of IAP antagonists. In vivo administration of IAP antagonists and α-GalCer resulted in increased IFNγ and IL-2 production from iNKT cells and decreased tumor burden in a mouse model of melanoma lung metastasis. Human iNKT cells also proliferated and increased IFNγ production dramatically in the presence of IAP antagonists, demonstrating the utility of these compounds in adoptive therapy of iNKT cells. Cancer Immunol Res; 6(1); 25-35. ©2017 AACR.
Insights
Inhibitor of apoptosis protein (IAP) antagonists selectively deplete invariant natural killer T (iNKT) cells during development, but enhance mature iNKT cell function. This suggests a complex role for IAP antagonists in cancer immunotherapy.
Area of Science:
- Immunology
- Cancer Biology
- Pharmacology
Background:
- Inhibitor of apoptosis protein (IAP) antagonists are investigated for cancer therapy.
- IAP antagonists synergize with anti-PD-1 immunotherapy in preclinical cancer models.
- Their primary impact is on immune cells, influencing antitumor immunity.
Purpose of the Study:
- To investigate the effects of IAP antagonism on T-cell development.
- To assess the impact on invariant natural killer T (iNKT) cells, crucial for cancer immunotherapy.
- To evaluate the potential of IAP antagonists in enhancing iNKT cell-based therapies.
Main Methods:
- Mouse fetal thymic organ culture to study T-cell development.
- Ex vivo culture of mature mouse and human iNKT cells.
- In vivo studies using a mouse model of melanoma lung metastasis.
- Analysis of cytokine production (IFNγ, IL-2) and tumor burden.
Main Results:
- IAP antagonism led to a selective loss of iNKT cells during thymic development, likely via TCR-mediated negative selection.
- Mature mouse and human iNKT cells showed enhanced cytokine production (IFNγ, IL-2) and proliferation upon IAP antagonist treatment.
- In vivo administration of IAP antagonists with α-GalCer reduced tumor burden in a melanoma metastasis model.
Conclusions:
- IAP antagonists have a dual effect: inhibiting iNKT cell development but enhancing mature iNKT cell effector functions.
- These findings highlight the complex immunomodulatory role of IAP antagonists.
- IAP antagonists show promise for enhancing adoptive iNKT cell therapy in cancer treatment.
