Reversing Immunotherapy Resistance in Ovarian Cancer by Targeting a Novel Immune-Suppressive Factor Released by Tumor-Associated Macrophages (TAMs)
[Technical Report, Annual Report]
Maine Medical Center
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Our studies suggest that a unique RGDKGE collagen fragment is generated within ovarian tumors. Given these and other current observations, the proposal was designed to test the central hypothesis that targeting the soluble RGDKGE collagen fragment may re-activate immune control of ovarian cancer and enhance the efficacy of immune checkpoint inhibitors by selectively disrupting a novel integrin-dependent signaling cascade. Data generated from our current studies suggest that integrin alpha-V beta-3 plays a role in regulating the expression of the immune checkpoint molecules LAG-3 and PD-L1. In particular, we provide evidence that the protein kinase FAK, but not Src plays an important role in regulating PD-L1 and LAG-3expression in T-cells. In addition, our new studies provide the first evidence that selective targeting of the RGDKGE collagen fragment may differentially alter the accumulation of distinct subsets of immune and stromal cells within specific tissue compartments in mice during tumor growth. Collectively, these novel observations may lead to the development of new treatment strategies for ovarian cancer and may lead to a better molecular understanding of how mechano-transduction signaling pathways regulate immune suppression.
- Medicine and Medical Research
- Anatomy and Physiology