CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages

Ball, Michael S.; Shipman, Emilie P.; Kim, Hyun-Jung; Liby, Karen T.; Pioli, Patricia A.

doi:10.1371/journal.pone.0149600

Cited by 31 publications

(31 citation statements)

References 62 publications

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“…2c, CDDO-Me treatment decreased MMP2 levels in TAMs. Moreover, CDDO-Me significantly attenuated expression of Arg1 in TAMs treated in vivo, as previously observed in vitro 12 . Increased levels of Arg1 are characteristic of alternatively activated macrophages and immunosuppressive TAMs.…”

Section: Cddo-me Confers Immunostimulatory Transcriptional Activationsupporting

confidence: 85%

“…In this regard, we recently demonstrated that the methyl ester of the synthetic triterpenoid 2-cyano-3,12-dixooleana- 1,9(11)dien-28-oic acid (CDDO-Me) repolarizes alternatively activated human macrophages and murine primary mammary TAMs from immunosuppressive to immunostimulatory 12 . CDDO-Me has been shown to strongly induce Nrf2 activation via Keap1 interaction and to upregulate anti-inflammatory and antioxidant pathways in cancer cells and cell lines 13,14 .…”

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confidence: 99%

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CDDO-Me Alters the Tumor Microenvironment in Estrogen Receptor Negative Breast Cancer

Ball¹,

Bhandari²,

Torres³

et al. 2020

Sci Rep

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the tumor microenvironment (tMe) is an essential contributor to the development and progression of malignancy. Within the tMe, tumor associated macrophages (tAMs) mediate angiogenesis, metastasis, and immunosuppression, which inhibits infiltration of tumor-specific cytotoxic CD8+ t cells. in previous work, we demonstrated that the synthetic triterpenoid cDDo-methyl ester (cDDo-Me) converts breast tAMs from a tumor-promoting to a tumor-inhibiting activation state in vitro. We show now that CDDO-Me remodels the breast TME, redirecting TAM activation and T cell tumor infiltration in vivo. We demonstrate that CDDO-Me significantly attenuates IL-10 and VEGF expression but stimulates TNF production, and reduces surface expression of CD206 and CD115, markers of immunosuppressive TAMs. CDDO-Me treatment redirects the TAM transcriptional profile, inducing signaling pathways associated with immune stimulation, and inhibits TAM tumor infiltration, consistent with decreased expression of CCL2. In CDDO-Me-treated mice, both the absolute number and proportion of splenic CD4 + t cells were reduced, while the proportion of CD8 + T cells was significantly increased in both tumors and spleen. Moreover, mice fed CDDO-Me demonstrated significant reductions in numbers of CD4 + Foxp3 + regulatory T cells within tumors. These results demonstrate for the first time that CDDO-Me relieves immunosuppression in the breast tMe and unleashes host adaptive anti-tumor immunity.The tumor microenvironment (TME) provides the interface for communication between malignant and immune cells. As cells accumulate genetic and epigenetic aberrations, they recruit immune and other cellular mediators that collectively establish chronic inflammation in the TME. Mounting evidence demonstrates that interaction between tumor cells and immune cells in the TME facilitates tumor immune evasion by redirecting immune cell activation from a state of immune stimulation to immune suppression.The activation state and effector function of tumor-associated lymphoid and myeloid cells are profoundly influenced by the local TME, and these cells are likely an essential component of most tumors, regardless of tumorigenic trigger 1,2 . Tumor associated macrophages (TAMs) are key orchestrators of tumor cell survival and metastasis and shape adaptive immune responses via interaction with CD4 + and CD8 + T cell populations, among others 3 . TAMs recruit monocytes to the TME by secreting chemokines including CCL2, and promote angiogenesis through production of vascular endothelial growth factor (VEGF) 4,5 , transforming growth factor β (TGF-β) and matrix metalloproteinases (MMPs) 6 . Immunosuppression in the TME is mediated by TAMs through production of TGF-β, IL-10, and arginase 1 7 , which inhibit T cell activation and survival.TAMs can account for up to 50% of the tumor mass in breast cancer and genetic depletion of TAMs results in delayed tumor progression 8 , indicating that these cells play a non-redundant role. High TAM volumes are associated with poor clinical outcome for s...

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Section: Cddo-me Confers Immunostimulatory Transcriptional Activationsupporting

confidence: 85%

mentioning

confidence: 99%

CDDO-Me Alters the Tumor Microenvironment in Estrogen Receptor Negative Breast Cancer

Ball¹,

Bhandari²,

Torres³

et al. 2020

Sci Rep

Self Cite

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“…In the experiments following an acute challenge with LPS (Figure 2), CDDO-Im suppressed levels of CCL2, which recruits monocytes to sites of inflammation, and VEGF, which promotes angiogenesis, in the pancreas. These findings mirror results we have obtained with the triterpenoid CDDO-Me; we have recently shown that CDDO-Me markedly attenuates CCL2 and VEGF expression in PyMT tumor associated macrophages both in vitro and in vivo (20). Elevated levels of both CCL2 (35), and VEGF (36) are poor prognostic indicators in patients with PDAC.…”

Section: Discussionsupporting

confidence: 84%

“…In this regard, our results suggest that CDDO-Im may enhance immune activation in PDAC by inhibiting immune-suppressive MDSC infiltration and by enhancing expression of T cellactivating cytokines, including IL-1β and TNFα (Supplementary Table 1, available at Carcinogenesis Online). Intriguingly, we have shown that CDDO-Me redirects activation of breast tumor associated macrophages from an M2 immune-suppressive to M1 immune-stimulatory phenotype (20). Although beyond the scope of the present study, our future work will determine whether CDDO-Im mediates similar effects on PDAC tumor associated macrophages.…”

Section: Discussionmentioning

confidence: 70%

“…In mice challenged with a low dose of LPS, CDDO-Me suppresses the production of proinflammatory cytokines and alters the composition of immune cell populations in the spleen; CDDO-Me also reduces the number of deaths in mice injected with lethal doses of LPS (17). Moreover, CDDO-Me suppresses angiogenesis in vivo (18), reduces the infiltration of TAMs into ER-mammary tumors in PyMT mice (19), reprograms TAMs from an M2 tumor promoting phenotype to an M1 tumor inhibiting phenotype (20) and inhibits the immunosuppressive activity of MDSCs in mice and in cancer patients (21). CDDO-Me is currently being tested in a Phase II clinical trial for the amelioration of pulmonary arterial hypertension; RTA408 (22), a second generation triterpenoid, is being evaluated for its ability to reprogram the immune system and attack tumors by inhibiting MDSC activation and activating cytotoxic T cells.…”

Section: Introductionmentioning

confidence: 99%

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The triterpenoid CDDO-imidazolide reduces immune cell infiltration and cytokine secretion in the Kras^G12D;Pdx1-Cre (KC) mouse model of pancreatic cancer

Leal

Sporn

Pioli

et al. 2016

CARCIN

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Because the 5-year survival rate for pancreatic cancer remains under 10%, new drugs are needed for the prevention and treatment of this devastating disease. Patients with chronic pancreatitis have a 12-fold higher risk of developing pancreatic cancer. LSL-Kras G12D/+ ;Pdx-1-Cre (KC) mice replicate the genetics, symptoms and histopathology found in human pancreatic cancer. Immune cells infiltrate into the pancreas of these mice and produce inflammatory cytokines that promote tumor growth. KC mice are particularly sensitive to the effects of lipopolysaccharide (LPS), as only 48% of KC mice survived an LPS challenge while 100% of wildtype (WT) mice survived. LPS also increased the percentage of CD45+ immune cells in the pancreas and immunosuppressive Gr1+ myeloid-derived suppressor cell in the spleen of these mice. The triterpenoid CDDO-imidazolide (CDDO-Im) not only reduced the lethal effects of LPS (71% survival) but also decreased the infiltration of CD45+ cells into the pancreas and the percentage of Gr1+ myeloid-derived suppressor cell in the spleen of KC mice 4-8 weeks after the initial LPS challenge. While the levels of inflammatory cytokine levels were markedly higher in KC mice versus WT mice challenged with LPS, CDDO-Im significantly decreased the production of IL-6, CCL-2, vascular endothelial growth factor and G-CSF in the KC mice. All of these cytokines are prognostic markers in pancreatic cancer or play important roles in the progression of this disease. Disrupting the inflammatory process with drugs such as CDDO-Im might be useful for preventing pancreatic cancer, especially in high-risk populations.

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Profibrotic Activation of Human Macrophages in Systemic Sclerosis

Bhandari

Ball

Martyanov

et al. 2020

Arthritis & Rheumatology

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CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages

Cited by 31 publications

References 62 publications

CDDO-Me Alters the Tumor Microenvironment in Estrogen Receptor Negative Breast Cancer

CDDO-Me Alters the Tumor Microenvironment in Estrogen Receptor Negative Breast Cancer

The triterpenoid CDDO-imidazolide reduces immune cell infiltration and cytokine secretion in the Kras^G12D;Pdx1-Cre (KC) mouse model of pancreatic cancer

Profibrotic Activation of Human Macrophages in Systemic Sclerosis

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CDDO-Me Redirects Activation of Breast Tumor Associated Macrophages

Cited by 31 publications

References 62 publications

CDDO-Me Alters the Tumor Microenvironment in Estrogen Receptor Negative Breast Cancer

CDDO-Me Alters the Tumor Microenvironment in Estrogen Receptor Negative Breast Cancer

The triterpenoid CDDO-imidazolide reduces immune cell infiltration and cytokine secretion in the KrasG12D;Pdx1-Cre (KC) mouse model of pancreatic cancer

Profibrotic Activation of Human Macrophages in Systemic Sclerosis

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The triterpenoid CDDO-imidazolide reduces immune cell infiltration and cytokine secretion in the Kras^G12D;Pdx1-Cre (KC) mouse model of pancreatic cancer