Intratumoral Myeloid Cells Regulate Responsiveness and Resistance to Antiangiogenic Therapy

Rivera, Lee B.; Meyronet, David; Hervieu, Valérie; Frederick, Mitchell J.; Bergsland, Emily K.; Bergers, Gabriele

doi:10.1016/j.celrep.2015.03.055

Cited by 132 publications

(153 citation statements)

References 76 publications

(63 reference statements)

Supporting

Mentioning

144

Contrasting

Order By: Relevance

“…Thus, we subdivided the CD11b + Gr1 + myeloid cells and analyzed these subpopulations separately (i.e., Ly6C high monocytes and Ly6G + neutrophils) based on their immunophenotype using appropriate surface markers. These CD11b + Gr1 + cells were previously implicated in resistance to anti-VEGF therapy (2,25). We also found abundant expression of CXCR4 in another monocyte subsetLy6C low monocytes-which do not belong to the CD11b + Gr1 + myeloid cells (Fig.…”

Section: Blockade Of Cxcr4 Enhances the Antitumor Effect Of Anti-vegfr2supporting

confidence: 52%

“…There have been several reports showing that TAMs mediate resistance to anti-VEGF therapy in different types of cancers (2,32). It is also known that VEGF inhibition promotes maturation and activation of DCs, which leads to an increase in intratumoral effector T-cell numbers (5).…”

Section: Discussionmentioning

confidence: 99%

“…A ntivascular endothelial growth factor (anti-VEGF) therapy is widely used in many types of solid tumors and is the current standard of care for metastatic colorectal cancer (CRC) (1). However, the beneficial effects from anti-VEGF therapy are often shortlived due to intrinsic resistance and/or resistance acquired during the treatment (1)(2)(3)(4)(5)(6)(7)(8). Therefore, it is critical to identify mechanisms and/or biomarkers of resistance to target these mechanisms and/or to stratify patients by biomarkers to improve the clinical outcome.…”

mentioning

confidence: 99%

See 2 more Smart Citations

Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer

Jung

Heishi

Incio

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

111

103

View full text Add to dashboard Cite

Antiangiogenic therapy with antibodies against VEGF (bevacizumab) or VEGFR2 (ramucirumab) has been proven efficacious in colorectal cancer (CRC) patients. However, the improvement in overall survival is modest and only in combination with chemotherapy. Thus, there is an urgent need to identify potential underlying mechanisms of resistance specific to antiangiogenic therapy and develop strategies to overcome them. Here we found that anti-VEGFR2 therapy up-regulates both C-X-C chemokine ligand 12 (CXCL12) and C-X-C chemokine receptor 4 (CXCR4) in orthotopic murine CRC models, including SL4 and CT26. Blockade of CXCR4 signaling significantly enhanced treatment efficacy of anti-VEGFR2 treatment in both CRC models. CXCR4 was predominantly expressed in immunosuppressive innate immune cells, which are recruited to CRCs upon anti-VEGFR2 treatment. Blockade of CXCR4 abrogated the recruitment of these innate immune cells. Importantly, these myeloid cells were mostly Ly6Clow monocytes and not Ly6Chigh monocytes. To selectively deplete individual innate immune cell populations, we targeted key pathways in Ly6Clow monocytes (Cx3cr1−/− mice), Ly6Chigh monocytes (CCR2−/− mice), and neutrophils (anti-Ly6G antibody) in combination with CXCR4 blockade in SL4 CRCs. Depletion of Ly6Clow monocytes or neutrophils improved anti-VEGFR2–induced SL4 tumor growth delay similar to the CXCR4 blockade. In CT26 CRCs, highly resistant to anti-VEGFR2 therapy, CXCR4 blockade enhanced anti-VEGFR2–induced tumor growth delay but specific depletion of Ly6G+ neutrophils did not. The discovery of CXCR4-dependent recruitment of Ly6Clow monocytes in tumors unveiled a heretofore unknown mechanism of resistance to anti-VEGF therapies. Our findings also provide a rapidly translatable strategy to enhance the outcome of anti-VEGF cancer therapies.

show abstract

Section: Blockade Of Cxcr4 Enhances the Antitumor Effect Of Anti-vegfr2supporting

confidence: 52%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer

Jung

Heishi

Incio

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

111

103

View full text Add to dashboard Cite

show abstract

“…Given the tight interplay between neutrophils and macrophages 131 , neutrophils may be expected to promote resistance to macrophage-targeting therapies. In fact, neutrophils have been shown to mediate resistance to the anti-angiogenic drug sorafenib after macrophages are blocked in the RIP1-Tag2 pancreatic and MMTV-PyMT mammary tumor mouse models 202 . Thus, targeting one myeloid cell population may require additional targeting of another myeloid cell population to counteract therapeutic resistance.…”

Section: Combining Neutrophil Targeting With Other Anti-cancer Therapiesmentioning

confidence: 99%

Neutrophils in cancer: neutral no more

2016

View full text Add to dashboard Cite

SummaryNeutrophils are indispensable antagonists of microbial infection and facilitators of wound healing. In the cancer setting, a newfound appreciation for neutrophils has come into view.The traditionally held belief that neutrophils are inert bystanders is being challenged by recent literature. Emerging evidence indicates that tumors manipulate neutrophils, sometimes early in their differentiation process, to create diverse phenotypic and functional polarization states able to alter tumor behavior. In this Review, we discuss the involvement of neutrophils in cancer initiation and progression, and their potential as clinical biomarkers and therapeutic targets. 2The name neutrophil -given to polymorphonuclear, granulocytic cells by Paul Ehrlich in the late 19th century -is based on the inability of these cells to retain acidic or basic dyes and for their preferential uptake of pH neutral dyes 1 . Although their neutral staining led to the identification of these cells, neutrophils in the cancer setting are anything but neutral.Neutrophils in tumor-bearing hosts can oppose or potentiate cancer progression. These two types of behavior are controlled by signals emanating from cancer cells or stromal cells within the tumor microenvironment, which educate neutrophils to execute the demise of the tumor or facilitate support networks that lead to its expansive spread. These functions can occur locally in or around the tumor microenvironment, as well as systemically in distant organs.Until the past few years, other immune cells such as macrophages have overshadowed the role of neutrophils in cancer. But recent studies and the development of new genetic tools have provided the cancer community with new insights into the profound influence of these dynamic cells by uncovering distinct capabilities for neutrophils throughout each step of carcinogenesis: from tumor initiation to primary tumor growth to metastasis.During these processes, neutrophils take on different phenotypes and sometimes opposing functions. Emerging evidence also indicates that these cells are highly influential, and are able to change the behavior of other tumor-associated cell types -primarily other immune cells. In this Review, we focus on how tumors manipulate the generation and release of neutrophils from the bone marrow. We discuss the mechanisms identified in animal models by which neutrophils participate in tumor initiation, growth and metastasis. Finally, we highlight the potential of these cells as clinical biomarkers and therapeutic targets. In humans, neutrophils are the most abundant immune cell population, representing 50-70% of all leukocytes. Over 10 11 neutrophils may be produced per day 2 , and tumors can increase this number by even more. Indeed, patients with various cancer types, including but not limited to breast, lung and colorectal cancer, often exhibit increased numbers of circulating neutrophils 3,4 . Recent studies have identified key pathways that tumors exploit to disrupt normal neutrophil homeostasis and these are discuss...

show abstract

“…In addition to promoting angiogenesis and vascular permeability, VEGF can also exert immunosuppressive effects in tumors (Figure 2). For example, VEGF inhibits maturation of DCs and induces accumulation of immunosuppressive inflammatory cells [56,57]. The complex mechanisms that may mediate anti-VEGF treatment resistance in HCC, and their implications for immunotherapy are discussed below.…”

Section: Vegf Overexpression In Cancer May Lead To Immunosuppressionmentioning

confidence: 99%

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

2016

View full text Add to dashboard Cite

Hepatocellular carcinoma (HCC) is a fatal disease with rising incidence in the world. For advanced HCC, sorafenib, a multikinase inhibitor, is the only systemic therapy with proven survival benefits. Sorafenib is a pan-VEGF receptor inhibitor, and thus many studies have focused its antivascular effects. But VEGF also acts as an immunosuppressive molecule. VEGF can inhibit maturation of dendritic cells, promote immune suppressive cell infiltration and enhance immune checkpoint molecules expression. On the other hand, potent VEGF inhibition may increase tumor hypoxia, which could hinder antitumor immunity or immunotherapy. Thus, achieving synergy when combining anti-VEGF therapy with immunotherapy may require proper polarization of the tumor microenvironment by dose titration or combination with other immunomodulating agents.

show abstract

Intratumoral Myeloid Cells Regulate Responsiveness and Resistance to Antiangiogenic Therapy

Cited by 132 publications

References 76 publications

Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer

Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer

Neutrophils in cancer: neutral no more

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

Contact Info

Product

Resources

About

Intratumoral Myeloid Cells Regulate Responsiveness and Resistance to Antiangiogenic Therapy

Cited by 132 publications

References 76 publications

Targeting CXCR4-dependent immunosuppressive Ly6C low monocytes improves antiangiogenic therapy in colorectal cancer

Targeting CXCR4-dependent immunosuppressive Ly6C low monocytes improves antiangiogenic therapy in colorectal cancer

Neutrophils in cancer: neutral no more

Rationally Combining Anti-VEGF Therapy with Checkpoint Inhibitors in Hepatocellular Carcinoma

Contact Info

Product

Resources

About

Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer

Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer