Browsing by Subject "Melanoma, Experimental"

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    Inhibition of estrogen signaling in myeloid cells increases tumor immunity in melanoma.
    (The Journal of clinical investigation, 2021-12) Chakraborty, Binita; Byemerwa, Jovita; Shepherd, Jonathan; Haines, Corinne N; Baldi, Robert; Gong, Weida; Liu, Wen; Mukherjee, Debarati; Artham, Sandeep; Lim, Felicia; Bae, Yeeun; Brueckner, Olivia; Tavares, Kendall; Wardell, Suzanne E; Hanks, Brent A; Perou, Charles M; Chang, Ching-Yi; McDonnell, Donald P
    Immune checkpoint blockade (ICB) therapies have significantly prolonged patient survival across multiple tumor types, particularly in melanoma. Interestingly, sex-specific differences in response to ICB have been observed, with males receiving a greater benefit from ICB than females, although the mechanism or mechanisms underlying this difference are unknown. Mining published transcriptomic data sets, we determined that the response to ICBs is influenced by the functionality of intratumoral macrophages. This puts into context our observation that estrogens (E2) working through the estrogen receptor α (ERα) stimulated melanoma growth in murine models by skewing macrophage polarization toward an immune-suppressive state that promoted CD8+ T cell dysfunction and exhaustion and ICB resistance. This activity was not evident in mice harboring macrophage-specific depletion of ERα, confirming a direct role for estrogen signaling within myeloid cells in establishing an immunosuppressed state. Inhibition of ERα using fulvestrant, a selective estrogen receptor downregulator (SERD), decreased tumor growth, stimulated adaptive immunity, and increased the antitumor efficacy of ICBs. Further, a gene signature that determines ER activity in macrophages predicted survival in patients with melanoma treated with ICB. These results highlight the importance of E2/ER signaling as a regulator of intratumoral macrophage polarization, an activity that can be therapeutically targeted to reverse immune suppression and increase ICB efficacy.
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    Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment.
    (J Clin Invest, 2013-09) Hanks, Brent A; Holtzhausen, Alisha; Evans, Katherine S; Jamieson, Rebekah; Gimpel, Petra; Campbell, Olivia M; Hector-Greene, Melissa; Sun, Lihong; Tewari, Alok; George, Amanda; Starr, Mark; Nixon, Andrew B; Augustine, Christi; Beasley, Georgia; Tyler, Douglas S; Osada, Takayu; Morse, Michael A; Ling, Leona; Lyerly, H Kim; Blobe, Gerard C
    Cancers subvert the host immune system to facilitate disease progression. These evolved immunosuppressive mechanisms are also implicated in circumventing immunotherapeutic strategies. Emerging data indicate that local tumor-associated DC populations exhibit tolerogenic features by promoting Treg development; however, the mechanisms by which tumors manipulate DC and Treg function in the tumor microenvironment remain unclear. Type III TGF-β receptor (TGFBR3) and its shed extracellular domain (sTGFBR3) regulate TGF-β signaling and maintain epithelial homeostasis, with loss of TGFBR3 expression promoting progression early in breast cancer development. Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-β signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity. Our findings provide mechanistic support for using TGF-β inhibitors to enhance the efficacy of tumor immunotherapy, indicate that sTGFBR3 levels could serve as a predictive immunotherapy biomarker, and expand the mechanisms by which TGFBR3 suppresses cancer progression to include effects on the tumor immune microenvironment.