Background
Ovarian cancer (OC) is a deadly disease with a high mortality rate due to its propensity for late detection and frequent recurrence. Following initial treatment, typically a combination of surgery and chemotherapy administration, patients often experience a disease remission but will likely experience a relapse. Once the disease has reached this recurrent state, therapies have limited efficacy. Identification of novel therapeutic targets and improved understanding of the molecular and cellular characteristics of the OC tumor microenvironment (TME) are urgently needed to advance treatment options for this devastating disease.
Methods
Here, we conducted a comprehensive analysis of tumor cells and the TME in 26 primary OC patient samples, including 16 chemonaive patients and 10 recurrent patients. Profiling antigens on tumor cells allowed for the identification of potential targets for the development of cell-based therapies, and profiling the TME in OC patients yielded insights into the differences between OC patients over the course of disease progression. In addition, we developed multiple cell-based immunotherapies to target OCs identified by various tumor antigens, including chimeric antigen receptor (CAR)-engineered T cell-based therapy, and allogeneic HSC-engineered invariant natural killer T (iNKT) cell-based therapy.1 2
Results
Our results demonstrated that our HSC-engineered iNKT(HSC-iNKT) cells exhibited robust antitumor efficacy in all patient-derived tumor cells tested, irrespective of the expression levels of tumor antigens and CSC markers, supporting the potential utility of HSC-iNKT cell therapy as a viable treatment option for OC, particularly in the setting of recurrent disease. In addition, the HSC-iNKT cells successfully targeted TAMs/MDSCs in our patient TME in a CD1d-dependent mechanism, while sparing healthy T cells, B cells, and NK cells, indicating their capacity to alter OC TME.
Conclusions
Overall, our study provides a detailed characterization of the tumor cell and TME profiles among primary OC patients and suggests the potential for developing cell-based therapies for the treatment of OC, particularly for recurrent disease.
Acknowledgements
We thank the University of California, Los Angeles (UCLA) CFAR Virology Core for providing human cells; and the UCLA BSCRC Flow Cytometry Core Facility for cell sorting support. This work was supported by a Director’s New Innovator Award from the NIH (DP2 CA196335, to L.Y.), a Partnering Opportunity for Translational Research Projects Award and a Partnering Opportunity for Discovery Stage Award from the California Institute for Regenerative Medicine (CIRM TRAN1–08533 and DISC2–11157, to L.Y.), a Discovery Stage Award from the California Institute for Regenerative Medicine (DISC2–13505 to L.Y. and S.M.), a Broad Stem Cell Research Center Innovative Award (to S.M.), a Stem Cell Research Award from the Concern Foundation (to L.Y.), a Research Career Development Award from the STOP CANCER Foundation (to L.Y.), a BSCRC-RHF Research Award from the Rose Hills Research Foundation (to L.Y.), and an Ablon Scholars Award (to L.Y.). Y.-R.L. is a postdoctoral fellow supported by a UCLA MIMG M. John Pickett Post-Doctoral Fellow Award.
References
Li YR, Wilson M, and Yang L. Target tumor microenvironment by innate T cells. Front Immunol. 2022; 13, 999549. 10.3389/fimmu.2022.999549
Li YR, Zhou Y, Kim YJ., Zhu Y, Ma F, Yu J, Wang YC, Chen X, Li Z, Zeng S, et al. Development of allogeneic HSC-engineered iNKT cells for off-the-shelf cancer immunotherapy. Cell Rep Med 2021; 2, 100449. 10.1016/j.xcrm.2021.100449.
Ethics Approval
This study was approved by the UCLA Office of the Human Research Protection Program, IRB #10–000727 and IRB #20–001659.
Consent
Primary OC patient samples were collected from consented patients through an IRB-approved protocol (IRB #10–000727) and processed.