Translational Adaptations in Macrophage for Ovarian Cancer Progression
Abstract
Rationale: Immunotherapy, like immune checkpoint inhibitors against PD-L1 and PD-1, has revolutionized cancer therapy. In contrast to other malignancies such as melanoma or renal cell cancer, immunotherapy has not been approved for ovarian cancer treatment. PD-L1 expression level can potentially predict immunotherapy efficacy. Despite the increasing availability of treatment approaches that target tumor immune surveillance in ovarian carcinoma, selecting patient groups that particularly benefit from these treatment modalities is clinically challenging as predictive biomarkers are lacking. The reason for the low response to immunotherapy in ovarian cancer remains unknown, which is a critical gap in our knowledge. Therefore, there is an immense need to delineate the mechanisms that abrogate or inhibit the actions of immunotherapy in ovarian cancer. Eukaryotic initiation factor 4E (eIF4E) is the major cap-binding protein that binds to the 5 cap of all eukaryotic messenger RNAs to promote protein synthesis. It has been shown that reducing the dose of eIF4E in vivo does not affect global protein synthesis and cellular homeostasis. On the contrary, eIF4E dose becomes rate-limiting and critical for translating unique networks of mRNAs following selective stress conditions such as those downstream of oncogenic signaling. However, the exact mechanism of how eiF4E affects tumor growth is not understood, which is a critical gap in our knowledge. This proposal will address this gap in knowledge by characterizing the mechanism of actions of eIF4E in ovarian cancer and its effect on macrophages in ovarian cancer. Understanding these mechanisms might make it possible to target eIF4E signaling pharmacologically. As a critical player in the tumor immune microenvironment, tumor-associated macrophages (TAMs) can stimulate tumor PD-L1 expression at the cellular level. TAMs are the key cells that create an immunosuppressive tumor microenvironment in many types of cancers. Notably, TAMs have been found to directly and indirectly modulate PD-1/PD-L1 expression in tumor immune microenvironment. Our data show increased uptake of eIF4E-EVs by macrophages with enhanced the PD-L1 expression. Based on our data, we hypothesize that tumor cells employ EVs to deliver eIF4E1 into the tumor microenvironment that drives translational reprogramming and immunosuppressive phenotype and promotes ovarian cancer growth and metastasis. Ovarian Cancer Advocacy Plans: A highly experienced ovarian cancer advocate, Ms. Sachia Powell, will participate in this research as the ovarian cancer advocate. Ms. Powell is an active participant and team captain in the Rivkin center SummeRun. Ms. Powell will bring the approaches she has used successfully in ovarian cancer advocacy to this grant. She will provide the patient perspective when research projects are designed and implemented and will be involved in all phases of the development of this proposal. Ms. Powell will be actively involved in all aspects of the proposed research program, including program evaluation and disseminating information to the public through her advocacy programs. Expected Outcome: With complementary expertise in the proposed approaches, our team reveals a novel mechanism by which eIF4E suppresses the immune system in ovarian cancer progression. This project will establish an unknown mechanism for eIF4E in the immune suppression of ovarian cancer progression. The scientific question and the proposed research are significant because we expect the completion of our studies to determine whether eIF4E could be used as biomarkers to predict immunotherapy outcomes. Apart from that, inhibiting eIF4E will provide an unprecedented opportunity to synergize sensitize PD-1 blockade in treating ovarian cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210138
Entities
People
- Sunila Pradeep
Organizations
- Medical College of Wisconsin
- United States Army