Figure 1. Dr Jelani Zarif, the Robert E. Meyerhoff endowed professor of oncology at Johns Hopkins School of Medicine, was one of the 11 Cancer Moonshot scholars named by the White House this year.

Figure 2. Members of Dr Zarif’s laboratory are testing the hypothesis that tumor-associated macrophages drive lethal prostate cancer metastasis and therapeutic resistance. Using surface markers and novel peptides will allow them to effectively target tumor-associated macrophages to induce antitumor immune responses.

Our group is ecstatic about being selected in the inaugural class of Cancer Moonshot scholars. This funding is my first R01 grant and builds upon work done in my K22 award mechanism. This will help us further understand the role of innate immune system that plays a role in driving prostate cancer progression and therapeutic resistance (Figure 1). Our funded proposal focuses on metastatic castration-resistant prostate cancer (mCRPC) tumors which are characterized by an abundant, tumor-promoting immune infiltrate that is composed of immune suppressive tumor-associated macrophages (TAMs). These cells promote angiogenesis, suppress T cell recruitment and/or activation, and promote metastasis. T cell exclusion by TAMs in mCRPC leads to resistance of immune checkpoint therapy. Therefore, there is an urgent need to develop innovative therapeutics that would target immune suppressive TAMs that will enhance responses to therapies and benefit mCRPC patients.

In our Cancer Moonshot proposal, we sought to reestablish an antitumor immune response by targeting surface receptors on TAMs that help drive prostate cancer progression. Using human prostate cancer tumor microarrays, we proposed that the macrophage mannose receptor (CD206) increased during prostate cancer progression to mCRPC.^1,2 Working with Dr Clayton Yates and colleagues, we selectively targeted CD206 using RP-182, a 10-mer amphipathic analog of host defense peptide that selectively induces a conformational switch of CD206 expressed on TAMs. RP-182–mediated induction of CD206 in human and murine TAMs elicits a program of endocytosis, phagosome-lysosome formation, and cancer cell phagocytosis, and reprograms immune-suppressive TAMs to an antitumor inflammatory phenotype. In syngeneic and autochthonous murine cancer models, RP-182 suppressed tumor growth, extended survival, and was an effective combination partner with chemo- or immune checkpoint therapy.³ In the proposed studies, we will evaluate the premise that CD206+ TAMs play an essential role in prostate cancer tumor progression and therapeutic resistance. We hypothesize that the immune-suppressive CD206-positive TAMs drive prostate cancer resistance to immunotherapies, and that therapeutic inhibition of CD206-positive TAMs will reeducate TAMs to the pro-inflammatory phenotype, enhance antitumor immune responses, and will synergize with chemo- or immune checkpoint therapy. The specific aims of this proposal are to establish the contribution of CD206-positive TAM function in prostate cancer tumorigenesis and immune evasion, elucidate how inhibition of CD206-positive TAMs may synergize with anti-PD-L1 to enhance antitumor immunity, and correlate CD206-positive TAM infiltrate with prostate cancer bone metastasis and patient outcomes. Utilizing a humanized mice and a novel syngeneic mCRPC mouse model in which tumors are heavily infiltrated with CD206-positive TAMs and refractory to immune checkpoint therapy, we will characterize the changes in adaptive and immune responses after CD206 is inhibited both in vitro and in vivo. We believe that targeting CD206-positive TAMs in syngeneic murine tumor models and patient-derived xenotransplantation models in humanized mice has great potential to alter the tumor microenvironment and enhance antitumor immune responses and may lead to novel therapeutics for mCRPC (Figure 2).