Immunosuppressive Factors Contributing to Immunotherapy Resistance in Endometrial Cancer with Deficient Mismatch Repair System
Abstract
Identifying factors that contribute to immunotherapy resistance in endometrial cancer (EC) patients with deficient mismatch repair system (dMMR): Immunotherapy with immune checkpoint inhibition (ICI) has emerged as a promising therapy in several cancers. A subset of endometrial cancer (about 30%) are characterized by certain genetic alteration called deficient mismatch repair and are highly responsive to immunotherapy with ICI. However, only 30%-50% of these patients do benefit from immunotherapy. Also, treatment with immunotherapy can lead to development of secondary resistance. Therefore, effective strategies are warranted to improve the overall benefit and reverse resistance to immunotherapy in dMMR EC. Targeting immunosuppressive factors within the tumor immune microenvironment (TME) represents an attractive approach. Our focus in this proposal is on tumor-associated macrophages in dMMR EC. Macrophages with a specific ’suppressor’ phenotype (M2 subtype) within TME play a significant role in promoting an immunosuppressive environment and in mediating therapy resistance. These cells are prominent in dMMR EC. However, another phonotype (M1 subtype) provides a favorable pro-inflammatory TME and enhance the immune response and synergize with ICI. Targeting macrophages and switching their phenotype from M2 to M1 is potentially promising approach that has not been investigated thoroughly before. Identifying dMMR EC patients who will likely respond to immunotherapy with ICI combined with therapy targeting macrophages: Immunotherapy with ICI is very attractive given the longstanding activity, durable response, and lower risks. Other predictive markers have been investigated but failed to identify subsets of patients who likely benefit from this approach. We have developed novel molecular signatures that correlate with resistance to ICI. The potential promise of these signatures is to identify patients who will not respond to ICI alone, but will benefit from them in combination with targeting immunosuppressive macrophages. Given the very high cost of these molecules (greater than $200,000/patient/year), there is also the real risk of financial toxicity for patients. Therefore, there is a clear unmet need for biomarkers to identify which dMMR EC patients harbor tumor with prominent immunosuppressive macrophages that will likely benefit from combination immunotherapy approach. Having such biomarkers will have significant impact, as it will allow us to identify the subset of these patients who will benefit from immunotherapy with durable response. At the same time, it will allow us to spare those who likely will not respond and spare them the time, effort, and side effects associated with the therapy, while also sparing them financial toxicity. We have shown that tumor associated macrophages, immune signatures related to CD47 and transforming growth factor-beta (TGF-beta) pathways are associated with lower survival outcome in dMMR EC and lower response to immunotherapy. The scientific premise of this project is to identify immune related pathways that contribute to immunotherapy resistance and can be reversed by targeted inhibition of these pathways. Further, molecular signature based on our 6-genes TGF-beta score and CD47 expression will predict resistance to ICI alone and identify patients who will benefit from targeted inhibition of TGF-beta or CD47 in combination with ICI. In this study, we propose to investigate the role of macrophages and immune pathways related to it in mediating resistance to immunotherapy. This can provide the basis for future studies to target these pathways. TGF-beta is known to mediate resistance to immunotherapy and to induce M2 subtype of macrophage. Furthermore, CD47 is utilized by tumor cells to escape ingestion by macrophage and CD47 thereby impairs the innate immune response. We hypothesize that immunotherapy resistance in dMMR EC may be mediated by immunosupp
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310807
Entities
People
- Haider Mahdi
Organizations
- UPMC Magee-Womens Hospital
- United States Army