Metastatic castration-resistant prostate cancer (mCRPC) tumors 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 in
mCRPC. T cells exclusion by TAMs in mCRPC leads to resistance of immune checkpoint therapy. Annually,
nearly 270,000 men will be diagnosed with prostate cancer (PCa) in the U.S. in 2021 and more than 33,000 men
will die from this disease. Therefore, mCRPC is an unmet medical need and 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. We sought to re-establish an anti-tumor immune response by targeting surface
receptors on TAMs that help drive PCa progression. Using human PCa tumor microarrays, we published that
the macrophage mannose receptor (CD206) increased during PCa progression to mCRPC. Our team then
selectively targeted of 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, phagosomelysosome formation, cancer cell
phagocytosis, and reprograms immune-suppressive TAMs to an anti-tumor 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. In the proposed studies, we
will evaluate the premise that CD206+ TAMs play an essential role in PCa tumor progression and therapeutic
resistance. We hypothesize that the immune-suppressive CD206+ TAMs drive PCa resistance to
immunotherapies and therapeutic inhibition of CD206+ TAMs will re-educate TAMs to the pro-inflammatory
phenotype, enhance anti-tumor immune responses and will synergize with chemo- or immune checkpoint
therapy. The specific aims of this proposal are: 1) Establish the contribution of CD206+ TAM function in PCa
tumorigenesis and immune evasion; 2) Elucidate how inhibition of CD206+ TAMs may synergize wirh anti-PD-
L1 to enhance anti-tumor immunity 3) Correlate CD206+ TAM infiltrate with Nivolumab response, PCa bone
metastasis and patient outcomes. Utilizing a humanized mice and a novel syngeneic mCRPC mouse model in
which tumors are heavily infiltrated with CD206+ 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.
In the third aim, we will measure CD206+ TAM expression in human PCa from mCRPC bone and single-cell
RNA sequenced PCa tumors from a Nivolumab clinical trial. Targeting CD206+ TAMs in syngeneic murine tumor
models and patient-derived xenotransplantation models in humanized mice has great potential to alter the tumor
microenvironment and enhance anti-tumor immune responses that may lead to novel therapeutics for mCRPC.
