Immunotherapy coordinated transcriptomic changes in ovarian tumor-macrophages for cancer treatment
Summary
Ovarian cancer (OC) remains one of most deadly diseases for women in the developed world. There is an unmet medical need to improve OC treatment outcome. OC tumor-associated macrophages (TAMs) play a key role shielding ovarian tumor from destruction. They immunosuppress anti-tumor T cell function and are associated with poor prognosis and treatment outcome. Here we will target them for OC treatment development with a virotherapeutic platform for the purpose.
The virotherapeutic platform is based on myxoma virus (MYXV), a novel oncolytic poxvirus that does not cause diseases in humans or mice, and can be used for immunotherapy. More importantly, MYXV favors binding and entry of TAMs to inhibit TAM functions, a surprising characteristic that makes it an excellent therapeutic tool. As MYXV is on the path for clinical testing, our work will provide invaluable guidelines for the trial design.
I have generated the therapeutic viral vector through targeted-knockout of M062R gene, a key viral immunoregulator, resulting in a replication-defective mutant (pending international patent “MYXOMA VIRUS COMPOSITIONS AND METHODS OF USE”, PCT/US2019/33973). The resulting viral agent is called ∆M062R. Infection with ∆M062R activates a newly identified anti-neoplastic pathway, called anti-tumor SAMD9 pathway. We found therapeutic benefit using ∆M062R in immunocompetent murine models of high-grade serious OC (HGSOC), the most common form of OC that causes death. Moreover, treatment of ∆M062R directly on patient TAMs eliminated OC TAM functions, and the treated TAMs activated specific anti-tumor T helper responses. The objective is to understand the immunotherapeutic benefit of this vector against TAMs through examining the transcriptomic remodeling by ∆M062R in immunosuppressive macrophages. Because the anti-neoplastic protein SAMD9 is linked to innate immune activation , we hypothesize that ∆M062R infection in immunosuppressive macrophages will lead to the activation of the proinflammatory cytokines that will reverse the M2 phenotype of TAMs for the activation of T helper cells against tumor antigen. Alternatively, ∆M062R infection in M2 macrophages will remodel the transcriptomic landscape to inactivate TAM function leading to a natural restoration of the T cell function. We will combine viral immunology, genomic, and bioinformatics for this study.
Aim 1. Characterize the transcriptomic outcome of ∆M062R treatment in a M2 macrophages model system. We (Liu and Cannon) established M2 model of human THP-1 cells and will utilize the state-of-the-art next generation RNA sequencing (RNAseq) to investigate the global transcriptional changes caused by ∆M062R treatment.
Aim 2. Identify novel transcriptomic modulators or pathways that are commonly associated with ∆M062R treatment benefit using patient TAMs. We have obtained ascites-macrophages from 4 de-identified OC patients (Cannon) for this study. Liu lab will process them for RNAseq and Peterson will provide bioinformatics analyses of the data.
Aim 3. We will validate novel host pathways identified commonly from Aim 1 and 2 in patient TAMs-T cell co-culture system and with modulators to the high confidence signature hits to test in the mouse models.
Impact: We will uncover novel mechanism(s) on eliminating immunosuppressive TAM functions and provide much needed guidelines on new treatment development for OC therapy.
Keywords:
- Cancer, metastasis, early diagnosis, circulating tumor cells, in vivo flow cytometry, photoacoustics
- Cancer
- Translational Research
Researchers:
- Jia Liu (Author)
- Martin Cannon
- Erich Peterson