Role of Angiopoietin-2 in Adaptive Tumor Resistance to VEGF Signaling Blockade

Rigamonti, Nicolò; Kadioglu, Ece; Keklikoglou, Ioanna; Rmili, Céline Wyser; Leow, Ching Ching; Palma, Michele De

doi:10.1016/j.celrep.2014.06.059

Cited by 210 publications

(191 citation statements)

References 46 publications

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“…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%

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.

110

103

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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.

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Section: Discussionmentioning

confidence: 99%

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.

110

103

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“…23,24 Ang2 has been described to provide compensatory tumor growth during anti-VEGF therapy. 25,26 Therefore, concurrent blockade of both VEGF and Ang2, as demonstrated by vanucizumab, 15 which is currently in a Phase 2 study (ClinicalTrials.gov NCT02141295) may result in improved anti-angiogenic efficacy not achievable with a single agent. We sought to determine whether the Bs4Ab design can be used to concurrently block VEGF and Ang2.…”

Section: Examples Of Antibodies Derived From the Bs4ab Technologymentioning

confidence: 99%

Insertion of scFv into the hinge domain of full-length IgG1 monoclonal antibody results in tetravalent bispecific molecule with robust properties

Bezabeh¹,

Fleming²,

Fazenbaker³

et al. 2016

mAbs

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By simultaneous binding two disease mediators, bispecific antibodies offer the opportunity to broaden the utility of antibody-based therapies. Herein, we describe the design and characterization of Bs4Ab, an innovative and generic bispecific tetravalent antibody platform. The Bs4Ab format comprises a full-length IgG1 monoclonal antibody with a scFv inserted into the hinge domain. The Bs4Ab design demonstrates robust manufacturability as evidenced by MEDI3902, which is currently in clinical development. To further demonstrate the applicability of the Bs4Ab technology, we describe the molecular engineering, biochemical, biophysical, and in vivo characterization of a bispecific tetravalent Bs4Ab that, by simultaneously binding vascular endothelial growth factor and angiopoietin-2, inhibits their function. We also demonstrate that the Bs4Ab platform allows Fc-engineering similar to that achieved with IgG1 antibodies, such as mutations to extend half-life or modulate effector functions.

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“…To date, 10 anti-VEGF drugs have been approved by the FDA to treat various solid tumors, starting with metastatic colorectal cancer (CRC) in 2004 (1). However, the survival benefit from these drugs is modest, as tumors develop resistance to these agents (3,4,(6)(7)(8)(9)(10)(11)(12)(13). The mechanisms of resistance remain far from understood.…”

Section: Introductionmentioning

confidence: 99%

Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy

Jung¹,

Heishi²,

Khan³

et al. 2017

Journal of Clinical Investigation

131

142

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Role of Angiopoietin-2 in Adaptive Tumor Resistance to VEGF Signaling Blockade

Cited by 210 publications

References 46 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

Insertion of scFv into the hinge domain of full-length IgG1 monoclonal antibody results in tetravalent bispecific molecule with robust properties

Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy

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Role of Angiopoietin-2 in Adaptive Tumor Resistance to VEGF Signaling Blockade

Cited by 210 publications

References 46 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

Insertion of scFv into the hinge domain of full-length IgG1 monoclonal antibody results in tetravalent bispecific molecule with robust properties

Ly6Clo monocytes drive immunosuppression and confer resistance to anti-VEGFR2 cancer therapy

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Product

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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