The tumor microenvironment has a strong impact on immune surveillance and the effector properties of macrophages. Macrophages recruited to tumors, a.k.a. tumor-associated macrophages (TAMs), show a M2-like phenotype of alternatively-activated cells (IL-12low, IL-23low, and IL-10high) that is believed to promote tumor growth and metastasis. Therefore, immunotherapies aimed at switching the M1/M2 balance toward M1 classically activated macrophages (IL-12high, IL-23high, and IL-10low) represent a valid strategy for the development of novel immunomodulatory approaches for the treatment of cancer patients. Various tumor-derived constituents may contribute to the immunosuppressive microenvironment of solid tumors, including anti-inflammatory cytokines, apoptotic bodies, prostaglandin E2 (PGE2), angiotensin II (Ang II), and others. In this regard, several experimental avenues are being explored in my lab in the context of immunomodulation and reprogramming of TAMs. The extraordinary intricacy of PGE2 effects in macrophages is complicated by multiple subtypes (EP1-4) of the PGE2 receptor, often coexpressed and operating in the same cell.
In order to study the immunosuppressive mechanisms of PGE2 in TAMs, EP2low and EP4low subclones of human THP-1 cells stably transfected with shRNA lentiviral vector plasmids capable of effective inhibition of EP2 and EP4, respectively, have been generated in my laboratory. In addition, THP-1 cells have been stably transfected with an NF-κB/AP-1-inducible reporter gene. Next, an in vitro model reproducing the tumor microenvironment and generating TAMs by co-culturing phorbol myristate acetate (PMA)-treated THP-1 cells (human macrophages) with PGE2- and Ang II-producing HCA-7 human carcinoma cells has been developed in my laboratory. The results obtained in the course of these studies strongly indicate that tumor-derived PGE2 may suppress the M1 inflammatory response in TAMs in an EP2-dependent manner, suggesting the potential efficacy of selective EP2 antagonists in the treatment of Cox-2+ tumors. Interestingly, targeted antagomir-mediated inhibition of miR21 and miR155 in THP-1 M may shift the M1/M2 balance and thus potentiate the anticancer activities of TAMs. PGE2-controlled mechanisms of expression of various Toll-like receptors (TLRs) and TLR-dependent activation of TAMs have been explored. It was found that tumor-derived PGE2 may inhibit the expression of TLRs in an EP2-dependent manner, whereas the EP4-signaling pathway may increase the expression and functional activity of TLRs in TAMs. Furthermore, using selective agonists and antagonists of AT1 and AT2 receptors for Ang II, it was uncovered that Ang II may well be involved in the immunosuppressive tumor microenvironment, suggesting the potential utility of Ang II receptor blockers for immunotherapy of Ang II-producing forms of cancer.

2022-present Professor of Immunology, Department of Basic Sciences, Kansas City University, Missouri, USA
2007-2022 Associate Professor, Department of Basic Sciences, Kansas City University, Missouri, USA
2000-2007 Assistant Professor, Department of Basic Medical Science, University of Missouri-Kansas City, Kansas City, MO, USA
1995-2000 Research Assiatant Professor, Dept. of Microbiology, Molecular Genetics
and Immunology, The University of Kansas Medical Center, Kansas City, KS, USA
1992-1995 Assistant Professor, Department of Emergency and Critical Care Medicine, Faculty of Medicine, U.A.E. University, Al Ain, United Arab Emirates
1989-1992 Visiting Scientist, Department of Clinical Bacteriology, Karolinska Institute, Stockholm, Sweden
1985-1988 Senior Scientist, Department of Cell and Molecular Biology, All-Union Cardiology Research Center, Academy of Medical Sciences of the USSR, Moscow, USSR

ORCID ID

http://orcid.org/0009-0000-8061-7825