MS4A in anti-tumor immunity - Project Summary/Abstract Immune checkpoint blockade (ICB) can provide long-term remission for patients across many cancer types. However, most patients do not respond for unclear reasons. Macrophages are a major component of the tumor microenvironment (TME) and dictate ICB response by regulating the degree of T cell recruitment and function, a strong predictor of ICB response. While early clinical trials targeting macrophages have shown promising results as monotherapy and combination therapy with ICB, larger phase III clinical trials have failed, suggesting we have an incomplete understanding of all the immunosuppressive signaling pathways in macrophages. Such pathways may be the key to specifically targeting and polarizing immunosuppressive macrophages into potent anti-tumor macrophages. Recently, membrane-spanning 4A (MS4A) member MS4A14, which is expressed primarily by macrophages, has been reported to be prognostic for worse survival in renal clear cell carcinoma via bioinformatic analysis. Remarkably, there is no literature that dissects the function/role of MS4A14 in mice or human, and its role in anti-tumor immunity is completely unknown. My bioinformatic analysis reveals that high MS4A14 mRNA levels are associated with worse patient survival across several cancer types and ICB non-responders have significantly higher macrophage expression of MS4A14 than responders. In macrophage cell lines, MS4A14 inhibits surface expression of major histocompatibility complex I and II (MHC-I/II) in response to classical inflammatory stimuli. Mechanistically, we find that MS4A14 is potently induced by stimuli which activate interferon regulatory factor 3 (IRF3), which is most well-known for inducing type I interferon, which plays a critical role macrophage activation and antigen presentation. Thus, MS4A14 may play previously unappreciated roles in regulating macrophage activation and functionality. This proposal hypothesizes that MS4A14 inhibits T cell activation by restricting macrophage antigen presentation and that this pathway is exploited in cancer to mediate immunosuppression and tumor progression. The long term goal is to identify novel mechanisms by which macrophages promote immunosuppression and dissect the function of MS4A14 in macrophages and anti-tumor immunity. Understanding this will advance the development and improve the efficacy of macrophage-based therapies in cancer by potentially identifying a new drug target. Aim 1 will determine whether MS4A14 deletion improves anti-tumor immunity and ICB responsiveness. Aim 2 will dissect the function(s) and mechanism(s) by which MS4A14 inhibits antigen-presentation and subsequent T cell immunity. Aim 3 will define the mechanism(s) by which MS4A14 is regulated in tumor-associated macrophages. Pursuing this fellowship will provide the PI with rigorous scientific and clinical training at a highly ranked and well-supported institution. This type of institutional, facility, and mentorship support will solidify the PI’s path towards becoming a pathologist-scientist who leads a world-class, independent translational tumor immunology research group.
