Immune-Mediated and Hypoxia-Regulated Programs: Accomplices in Resistance to Anti-angiogenic Therapies
Immune-Mediated and Hypoxia-Regulated Programs: Accomplices in Resistance to Anti-angiogenic Therapies
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DOI：
10.1007/164_2017_29
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发表时间：
2018-01-01
期刊：
影响因子：
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通讯作者：
Rabinovich, Gabriel A.
中科院分区：
文献类型：
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作者：
Croci, Diego O.;Mendez-Huergo, Santiago P.;Rabinovich, Gabriel A.
与化疗或其他靶向治疗耐药过程中发生的机制相反，对血管生成阻断的代偿适应并不意味着编码药物靶点或多药耐药机制的基因发生突变改变，而是涉及代偿血管生成途径的内在或获得性激活。在本文中，我们强调了在血管内皮生长因子（VEGF）阻断的情况下，缺氧调节和免疫介导的内皮细胞程序和维持血管生成的机制。这些机制包括骨髓细胞群的动员和细胞因子和趋化因子驱动电路的激活，这些电路在抗血管生成治疗的内在和获得性抵抗过程中运行。特别地，我们关注的发现强调了凝集素和糖基化配体在促进抗vegf治疗的耐药性中的作用，并讨论了克服或减弱这种代偿途径的可能策略。最后，我们强调了肿瘤微环境（TME）中免疫抑制和促血管生成程序之间相互作用的新证据，并讨论了旨在同时增强抗肿瘤免疫反应和抵消异常血管生成的新组合抗癌策略。
In contrast to mechanisms taking place during resistance to chemotherapies or other targeted therapies, compensatory adaptation to angiogenesis blockade does not imply a mutational alteration of genes encoding drug targets or multidrug resistance mechanisms but instead involves intrinsic or acquired activation of compensatory angiogenic pathways. In this article we highlight hypoxia-regulated and immune-mediated mechanisms that converge in endothelial cell programs and preserve angiogenesis in settings of vascular endothelial growth factor (VEGF) blockade. These mechanisms involve mobilization of myeloid cell populations and activation of cytokine- and chemokine-driven circuits operating during intrinsic and acquired resistance to anti-angiogenic therapies. Particularly, we focus on findings underscoring a role for galectins and glycosylated ligands in promoting resistance to anti-VEGF therapies and discuss possible strategies to overcome or attenuate this compensatory pathway. Finally, we highlight emerging evidence demonstrating the interplay between immunosuppressive and pro-angiogenic programs in the tumor microenvironment (TME) and discuss emerging combinatorial anticancer strategies aimed at simultaneously potentiating antitumor immune responses and counteracting aberrant angiogenesis.