Abstract 3653: Oncostatin m receptor signaling reprograms tumor microenvironment for chemoresistance
Authors: Geethadevi Anjali , Tsaih Shirng-Wern , Nair Ajay , Ku Zhiqiang , Kadamberi Ishaque Pulikkal , Parashar Deepak , Gupta Prachi , Kumar Sudhir , George Jasmine , Mittal Sonam , Bradley William , Schwabe Robert F. , An Zhiqiang , Zhang Ningyan , Pradeep Sunila , Raghavan Pradeep Chaluvally 
Published: June 2023

Introduction: High-grade serous ovarian carcinoma (HGSOC) is the most lethal gynecological malignancy and accounts for ~70% of tumor recurrences after standard chemotherapy and immunotherapy. Ovarian tumor microenvironment (TME) is undeniably complex which presents considerable challenge in understanding the immunotherapy treatment responses. Our previous study has revealed that Oncostatin M receptor (OSMR) is highly expressed in ovarian cancer cells and cancer associated fibroblasts (CAFs), whereas its ligand OSM is predominantly expressed in tumor associated macrophages (TAMs). This study aims to investigate how the OSM-OSMR paracrine signaling between tumor cells, CAFs and TAMs reprograms the TME to influence therapeutic responses in ovarian cancer.

Methods: We employed a 3D-3-cell co-culture method in vitro to understand how OSM/OSMR signaling modulates the interactions between ovarian cancer cells, CAFs and TAMs, that can impact therapy response of cisplatin resistant cancer cells in the ovarian TME. We performed RNA sequencing to study the differential gene signatures of each cell component in a 3-cell co-culture with their monolayer counterparts. This system was also challenged with chemotherapy-cisplatin and immunotherapy such as our newly developed anti-OSMR monoclonal antibodies to assess the therapy response of each cell component.

Results: Using single-cell and single-nuclear RNA seq dataset analyses of 17 human HGSOC patient ascites, we found that CAFs and TAMs are the predominant stromal or immune cell population enriched in ovarian cancer tissues. Using immunofluorescence, we identified that enrichment of CAFs along with extracellular matrix proteins surrounding tumor cells as an indication of heavily desmoplastic tumors. Using tumor-infiltrating immune cells dataset-TIMER, we found that high OSMR in cancer cells or CAFs along with high OSM in TAMs are associated with poor survival in ovarian cancer patients. Further, RNA sequencing data of 3-cell coculture models revealed an invasive, desmoplastic and immune-suppressive gene signature compared to independent culture conditions. Notably, CAFs and ovarian cancer cells co-cultured with TAMs exhibited an improved activation of JAK/STAT3 and PI3K-AKT oncogenic pathways for chemoresistance in ovarian cancer cells.

Conclusions: Our preliminary findings uncovered a potential mechanism of action of OSM-OSMR signaling in reprogramming ovarian cancer cells and stromal fibroblasts in ovarian cancer TME. Importantly, we highlight the importance of crosstalk between CAFs, ovarian cancer cells and TAMs for harnessing OSM/OSMR signaling for chemoresistance in cancer cells. Our findings also demonstrated the potential of anti-OSMR antibody therapy to target cancer cells and CAFs in the tumor microenvironment for abrogating desmoplasia; thus, improving chemosensitivity.

Citation Format: Anjali Geethadevi, Shirng-Wern Tsaih, Ajay Nair, Zhiqiang Ku, Ishaque Pulikkal Kadamberi, Deepak Parashar, Prachi Gupta, Sudhir Kumar, Jasmine George, Sonam Mittal, William Bradley, Robert F. Schwabe, Zhiqiang An, Ningyan Zhang, Sunila Pradeep, Pradeep Chaluvally Raghavan. Oncostatin m receptor signaling reprograms tumor microenvironment for chemoresistance. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3653.