Targeting tumor-associated macrophages to combat pancreatic cancer

Cui, Ran; Yang, Wen; Lattime, Edmund C.; Stein, Mark N.; Xu, Qing; Tan, Xi

doi:10.18632/oncotarget.9383

Cited by 80 publications

(70 citation statements)

References 185 publications

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“…4,34 The transition of M1-TAM to M2-TAM is another aspect of immune response during the progression of PDAC, as the accumulation of M2-TAM is evident in PDAC. 30 The present study indicates that VASH2 is responsible for the modulation of tumor immunity through accumulation of M2-TAM as well.…”

Section: Discussionsupporting

confidence: 52%

“…Indeed, CXCR2 signaling is reported be responsible for the accumulation of MDSC in PDAC, and blockade of CXCR2 signaling contributes to improved tumor immunity and reduced metastasis of PDAC in mice . The transition of M1‐TAM to M2‐TAM is another aspect of immune response during the progression of PDAC, as the accumulation of M2‐TAM is evident in PDAC . The present study indicates that VASH2 is responsible for the modulation of tumor immunity through accumulation of M2‐TAM as well.…”

Section: Discussionsupporting

confidence: 52%

“…Macrophages are broadly divided into proinflammatory M1-TAM and anti-inflammatory M2-TAM. 30 We showed that deletion of the Vash2 gene caused significant reduction of Arginase-1 positive M2-TAM in PDAC ( Figure S5).…”

Section: Vasohibin-2 Is Involved In the Evasion Of Tumor Immunitymentioning

confidence: 87%

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Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

et al. 2019

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Vasohibin‐2 (VASH2) is expressed in various cancers and promotes their progression. We recently reported that pancreatic cancer patients with higher VASH2 expression show poorer prognosis. Herein, we sought to characterize the role of VASH2 in pancreatic cancer. We used LSL‐KrasG12D; LSL‐Trp53R172H; Pdx‐1‐Cre (KPC) mice, a mouse model of pancreatic ductal adenocarcinoma (PDAC), and cells isolated from them (KPC cells). Knockdown of Vash2 from PDAC cells did not affect their proliferation, but decreased their migration. When Vash2‐knockdown PDAC cells were orthotopically inoculated, liver metastasis and peritoneal dissemination were reduced, and the survival period was significantly prolonged. When KPC mice were crossed with Vash2‐deficient mice, metastasis was significantly decreased in Vash2‐deficient KPC mice. VASH2 was recently identified to have tubulin carboxypeptidase activity. VASH2 knockdown decreased, whereas VASH2 overexpression increased tubulin detyrosination of PDAC cells, and tubulin carboxypeptidase (TCP) inhibitor parthenolide inhibited VASH2‐induced cell migration. We next clarified its role in the tumor microenvironment. Tumor angiogenesis was significantly abrogated in vivo when VASH2 was knocked down or deleted. We further examined genes downregulated by Vash2 knockdown in KPC cells, and found chemokines and cytokines that were responsible for the recruitment of myeloid derived suppressor cells (MDSC). Indeed, MDSC were accumulated in PDAC of KPC mice, and they were significantly decreased in Vash2‐deficient KPC mice. These findings suggest that VASH2 plays an essential role in the metastasis of PDAC with multiple effects on both cancer cells and the tumor microenvironment, including tubulin detyrosination, tumor angiogenesis and evasion of tumor immunity.

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Section: Discussionsupporting

confidence: 52%

Section: Discussionsupporting

confidence: 52%

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Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

et al. 2019

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“…CCL2-positive TAM comprises close to 30% of the tumor-infiltrating lymphocytes (TILs) in the TME of PDA patients and vastly outnumbers cytotoxic T-cells [34•]. In murine models of PDA treated with an anti-CCR2 (the receptor of CCL2) agent, markedly less TAM infiltration and greater cytotoxic T-cell infiltration was appreciated.…”

Section: Transforming the Tmementioning

confidence: 99%

Harnessing the Immune System in Pancreatic Cancer

Das

Berlin

Cardin

2018

Curr. Treat. Options in Oncol.

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Managing patients with metastatic pancreatic adenocarcinoma (mPDA) is a challenging proposition for any treating oncologist. Although the potency of first-line therapies has improved with the approvals of FOLFIRINOX and gemcitabine plus nab-paclitaxel, many patients are unable to derive significant benefit from later lines of therapy upon progression. Enrollment on clinical trials remains among the best options for patients with mPDA in all lines of therapy. At our institution, we routinely check for microsatellite instability (MSI-H) and perform next-generation sequencing (NGS) at the time of diagnosis in all good performance status mPDA patients. Although MSI-H status is only found in 1% of patients with mPDA, given pembrolizumab's tissue-agnostic approval for MSI-H tumors in later-line settings, it is a viable option when deciding on subsequent lines of therapy. Any use of immune therapy in mPDA is investigational outside the MSI-H setting. NGS can identify BRCA or other DNA damage response (DDR) defects in patients which can predict sensitivity to platinum-based therapies and influence choice of both initial and later lines of therapy. It can also identify rare actionable genomic alterations such as HER2 (2%) and TRK fusions (0.1%) and offer patients the option of enrollment on clinical trials with agents targeting these or other identified alterations. We believe enrolling mPDA patients on clinical trials with immune-modulating agents is critical to determine if there are other patient subsets, outside of the MSI-H setting, who would benefit from these approaches. Immunotherapy's general tolerability and potential to generate durable responses make it particularly appealing for mPDA patients. Although single-modality immunotherapy such as checkpoint inhibitors or vaccines have not demonstrated efficacy in this disease, combinatorial strategies targeting unique aspects of PDA including the tumor microenvironment and desmoplastic stroma have shown preclinical or early-phase success. Validating these treatments with later-phase prospective studies is essential to making immunotherapy a routine component of the treatment armamentarium for mPDA patients.

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“…The findings suggest that immune stromal cells (mainly monocytes and macropahges) are also an important source of LL-37 [42][43][44][45], and that cancer cells may manipulate the immune stromal cells into producing the LL-37 that they need.…”

Section: Introductionmentioning

confidence: 99%

Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer

Chen

Zou

et al. 2018

Cell Physiol Biochem

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LL-37, the C-terminal peptide of human cathelicidin antimicrobial peptide (CAMP, hCAP18), reportedly increases resistance to microbial invasion and exerts important physiological functions in chemotaxis, promotion of wound closure, and angiogenesis. Accumulating evidence indicates that LL-37 also plays a significant role in human cancer. LL-37 induces tumorigenic effects in cancers of the ovary, lung, breast, prostate, pancreas, as well as in malignant melanoma and skin squamous cell carcinoma. In contrast, LL-37 displays an anti-cancer effect in colon cancer, gastric cancer, hematologic malignancy and oral squamous cell carcinoma. Mechanistically, LL-37-induced activation of membrane receptors and subsequent signaling pathways lead to alteration of cellular functions. Different membrane receptors on various cancer cells appear to be responsible for the tissue-specific effects of LL-37. Meanwhile, the findings that vitamin D-dependent induction of cathelicidin in human macrophages activates the anti-cancer activity of tumor-associated macrophages (TAMs) and enhances antibody-dependent cellular cytotoxicity (ADCC) support critical roles of vitamin D-dependent induction of cathelicidin in cancer progression. This review describes novel advances involving the roles and mechanisms of human cathelicidin LL-37 in cancer.

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Targeting tumor-associated macrophages to combat pancreatic cancer

Cited by 80 publications

References 185 publications

Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

Vasohibin‐2 plays an essential role in metastasis of pancreatic ductal adenocarcinoma

Harnessing the Immune System in Pancreatic Cancer

Roles and Mechanisms of Human Cathelicidin LL-37 in Cancer

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