The Next Hurdle in Cancer Immunotherapy: Overcoming the Non-T-Cell-Inflamed Tumor Microenvironment.
The Next Hurdle in Cancer Immunotherapy: Overcoming the Non-T-Cell-Inflamed Tumor Microenvironment.
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DOI：
10.1053/j.seminoncol.2015.05.011
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发表时间：
2015-08
影响因子：
4
通讯作者：
Gajewski TF
中科院分区：
文献类型：
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作者：
Gajewski TF
越来越多的证据表明，晚期实体瘤患者的一个主要子集显示了T细胞炎症肿瘤微环境的证据。这种表型对几种类型的早期癌症具有积极的预后价值，表明宿主产生抗肿瘤免疫应答的尝试反映了与改善患者结局相关的生物学过程。在转移性疾病中，这种表型的存在似乎与对几种免疫疗法的临床应答相关，包括癌症疫苗、检查点阻断和过继性T细胞转移。随着对这些疗法中的几种的高临床应答率，沿着早期数据表明组合免疫疗法可能甚至更有效，有效的基于免疫的疗法似乎可能对于患有一系列不同癌症的患者成为现实，这些癌症在生理上支持个体亚组中的T细胞发炎的肿瘤微环境。因此，下一个重要的障碍之一将是开发新的治疗干预措施，使这些免疫疗法在非T细胞炎症表型患者中有效。这种干预措施的合理开发将受益于对解释T细胞炎症肿瘤微环境存在或不存在的机制的详细分子理解，这反过来又将受益于对患者样本的集中询问。这种反复的“反向翻译”研究策略已经确定了新的候选治疗靶点和方法。据设想，这些研究的最终结果将是一系列扩大的干预措施，这将扩大从临床免疫治疗中受益的患者比例。
A growing body of evidence suggests that a major subset of patients with advanced solid tumors shows evidence for a T cell-inflamed tumor microenvironment. This phenotype has positive prognostic value for several types of early stage cancer, suggesting that the attempt by the host to generate an anti-tumor immune response reflects a biologic process associated with improved patient outcomes. In metastatic disease, the presence of this phenotype appears to be associated with clinical response to several immunotherapies, including cancer vaccines, checkpoint blockade, and adoptive T cell transfer. With the high rate of clinical response to several of these therapies, along with early data indicating that combination immunotherapies may be even more potent, it seems likely that effective immune-based therapies will become a reality for patients with a range of different cancers that physiologically support the T cell-inflamed tumor microenvironment in a subset of individuals. Therefore, one of the next significant hurdles will be to develop new therapeutic interventions that will enable these immunotherapies to be effective in patients with the non-T cell-inflamed phenotype. Rational development of such interventions will benefit from a detailed molecular understanding of the mechanisms that explain the presence or absence of the T cell-inflamed tumor microenvironment, which in turn will benefit from focused interrogation of patient samples. This iterative “reverse-translational” research strategy has already identified new candidate therapeutic targets and approaches. It is envisioned that the end result of these investigations will be an expanded array of interventions that will broaden the fraction of patients benefitting from immunotherapies in the clinic.