Melo Vinicio, Bremer Edwin, Martin John D
Department of Hematology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.
Materia Therapeutics, Las Vegas, NV, United States.
Front Cell Dev Biol. 2022 May 30;10:908389. doi: 10.3389/fcell.2022.908389. eCollection 2022.
Immunotherapies modulate the function of immune cells to eradicate cancer cells through various mechanisms. These therapies are successful across a spectrum of cancers, but they are curative only in a subset of patients. Indeed, a major obstacle to the success of immunotherapies is the immunosuppressive nature of the tumor microenvironment (TME), comprising the stromal component and immune infiltrate of tumors. Importantly, the TME in most solid cancers is characterized by sparsely perfused blood vessels resulting from so-called pathological angiogenesis. In brief, dysregulated development of new vessels results in leaky tumor blood vessels that inefficiently deliver oxygen and other nutrients. Moreover, the occurrence of dysregulated fibrosis around the lesion, known as pathological desmoplasia, further compresses tumor blood vessels and impairs blood flow. TME normalization is a clinically tested treatment strategy to reverse these tumor blood vessel abnormalities resulting in stimulated antitumor immunity and enhanced immunotherapy efficacy. TME normalization includes vascular normalization to reduce vessel leakiness and reprogramming of cancer-associated fibroblast to decompress vessels. How immunotherapies themselves normalize the TME is poorly understood. In this review, we summarize current concepts and progress in TME normalization. Then, we review observations of immunotherapy-induced TME normalization and discuss the considerations for combining vascular normalizing and immunotherapies. If TME could be more completely normalized, immunotherapies could be more effective in more patients.
免疫疗法通过多种机制调节免疫细胞的功能以根除癌细胞。这些疗法在多种癌症中都取得了成功，但仅对一部分患者具有治愈效果。事实上，免疫疗法成功的一个主要障碍是肿瘤微环境（TME）的免疫抑制特性，肿瘤微环境由肿瘤的基质成分和免疫浸润组成。重要的是，大多数实体癌中的肿瘤微环境的特征是由所谓的病理性血管生成导致的血管灌注稀疏。简而言之，新血管的发育失调导致肿瘤血管渗漏，无法有效地输送氧气和其他营养物质。此外，病变周围出现失调的纤维化，即病理性促结缔组织增生，进一步压迫肿瘤血管并损害血流。肿瘤微环境正常化是一种经过临床测试的治疗策略，旨在逆转这些肿瘤血管异常，从而刺激抗肿瘤免疫并提高免疫治疗效果。肿瘤微环境正常化包括血管正常化以减少血管渗漏，以及对癌症相关成纤维细胞进行重编程以解除血管压迫。免疫疗法本身如何使肿瘤微环境正常化目前尚不清楚。在这篇综述中，我们总结了肿瘤微环境正常化的当前概念和进展。然后，我们回顾了免疫疗法诱导肿瘤微环境正常化的观察结果，并讨论了联合血管正常化疗法和免疫疗法的注意事项。如果肿瘤微环境能够更完全地正常化，免疫疗法可能会在更多患者中更有效。
