Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression

Zhu, Yu; Herndon, John M.; Sojka, Dorothy K.; Kim, Ki Wook; Knolhoff, Brett L.; Zuo, Chong; Cullinan, Darren R.; Luo, Jingqin; Bearden, Audrey R.; Lavine, Kory J.; Yokoyama, Wayne M.; Hawkins, William G.; Fields, Ryan C.; Randolph, Gwendalyn J.; DeNardo, David G.

doi:10.1016/j.immuni.2017.07.014

Cited by 566 publications

(575 citation statements)

References 37 publications

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“…Emerging literature suggests that tissue‐resident TAMs originating from the yolk sac have distinct functions compared to macrophages originating from bone‐marrow derived monocytes . At this point it would be premature to discuss, or even speculate, whether the described phenotypic TAM subpopulations (i.e., streaming, perivascular, premetastatic) are associated with committed monocyte progenitors originating from the bone marrow, or whether they represent denizens traceable back to their yolk sac predecessors.…”

Section: Discussionmentioning

confidence: 99%

“…In pancreatic ductal adenocarcinoma (PDAC) for example, a proportion of TAMs, shown to be of embryonic origin, assumes functions independent of bone marrow‐derived monocytes . In transgenic K‐ras LSL‐G12D/+/ p53 R127H/+ /PdxCre harboring PDAC tumors, these tissue‐resident macrophages are capable of proliferation and self‐expansion, and they express high levels of pro‐fibrotic ECM‐remodeling factors that facilitate tumor progression . Importantly, the suppression of the CSF1/CSF1R axis in this tumor model does not significantly affect this TAM subpopulation (although it partially reduces tumor size), suggesting that PDAC progression is in part regulated by tissue‐resident TAMs …”

Section: Introductionmentioning

confidence: 91%

“…Although the pathways describing infiltration and maturation of bone marrow‐derived monocytes are well established, tissue‐resident macrophages of embryonic origin (i.e., those derived from the yolk sac and/or fetal liver) also contribute significantly to the TAM population. In pancreatic ductal adenocarcinoma (PDAC) for example, a proportion of TAMs, shown to be of embryonic origin, assumes functions independent of bone marrow‐derived monocytes . In transgenic K‐ras LSL‐G12D/+/ p53 R127H/+ /PdxCre harboring PDAC tumors, these tissue‐resident macrophages are capable of proliferation and self‐expansion, and they express high levels of pro‐fibrotic ECM‐remodeling factors that facilitate tumor progression .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

Sanchez

Borriello

Entenberg

et al. 2019

Journal of Leukocyte Biology

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Macrophages represent a heterogeneous group of cells, capable of carrying out distinct functions in a variety of organs and tissues. Even within individual tissues, their functions can vary with location. Tumor‐associated macrophages (TAMs) specialize into three major subtypes that carry out multiple tasks simultaneously. This is especially true in the context of metastasis, where TAMs establish most of the cellular and molecular prerequisites for successful cancer cell dissemination and seeding to the secondary site. Perivascular TAMs operate in the perivascular niche, where they promote tumor angiogenesis and aid in the assembly of intravasation sites called tumor microenvironment of metastasis (TMEM). Streaming TAMs co‐migrate with tumor cells (irrespective of the perivascular niche) and promote matrix remodeling, tumor cell invasiveness, and an immunosuppressive local microenvironment. Premetastatic TAMs are recruited to the premetastatic niche, where they can assist in tumor cell extravasation, seeding, and metastatic colonization. The dynamic interplay between TAMs and tumor cells can also modify the ability of the latter to resist cytotoxic chemotherapy (a phenotype known as environment‐mediated drug resistance) and induce chemotherapy‐mediated pro‐metastatic microenvironmental changes. These observations suggest that future therapeutics should be designed to target TAMs with the aim of suppressing the metastatic potential of tumors and rendering chemotherapy more efficient.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

Sanchez

Borriello

Entenberg

et al. 2019

Journal of Leukocyte Biology

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show abstract

“…Recent data in mice suggest that the immunological origin of TAMs (yolk sac or monocyte derived) can substantially affect their overall suppressiveness. In studies of spontaneous mouse PDAC, yolk-sac-derived tumor-associated macrophages (YS-TAMs), which are seeded into tissues in early development and thus before malignant transformation, have been shown to be more tumor supporting than monocyte-derived TAMs 51 (Fig. 3b).…”

Section: Analyzing Progressive Development Of the Time At Primary Andmentioning

confidence: 99%

Understanding the tumor immune microenvironment (TIME) for effective therapy

Binnewies

Roberts

Kersten

et al. 2018

Nat Med

3,826

3,180

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The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient’s tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.

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“…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. Tumors from anti-CCR2-treated mice also demonstrated a gene expression profile shift from Th2 to Th1, characterized by an increase in IFN-Y-mediated signaling [35]. In CCL5 knockout murine PDA models, 50% less TReg were noted in harvested tumors compared to tumors from WT models.…”

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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Tissue-Resident Macrophages in Pancreatic Ductal Adenocarcinoma Originate from Embryonic Hematopoiesis and Promote Tumor Progression

Cited by 566 publications

References 37 publications

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

The emerging roles of macrophages in cancer metastasis and response to chemotherapy

Understanding the tumor immune microenvironment (TIME) for effective therapy

Harnessing the Immune System in Pancreatic Cancer

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