Cancer Immunotherapy Targets Based on Understanding the T Cell-Inflamed Versus Non-T Cell-Inflamed Tumor Microenvironment.
Cancer Immunotherapy Targets Based on Understanding the T Cell-Inflamed Versus Non-T Cell-Inflamed Tumor Microenvironment.
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DOI：
10.1007/978-3-319-67577-0_2
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发表时间：
2017
影响因子：
--
通讯作者：
Spranger S
中科院分区：
文献类型：
--
作者：
Gajewski TF;Corrales L;Williams J;Horton B;Sivan A;Spranger S
大多数癌症表达的肿瘤抗原可以被宿主的T细胞识别。然而，癌症在临床上变得明显这一事实表明，免疫逃逸肯定会发生。基于基因表达谱，已经确定了人类黑色素瘤转移的两个主要亚组。其中一个亚群具有T细胞炎症表型，包括趋化因子、T细胞标记物和I型干扰素的表达。相比之下，另一个主要亚群缺乏这种表型，并被指定为非T细胞炎症。这两种表型的免疫逃逸机制可能是不同的，因此促进临床反应所需的最佳免疫治疗干预可能是不同的。T细胞炎症的肿瘤微环境亚群表现出最高的负性调节因子表达，包括PD-L1、IDO、FoxP3+Tregs，以及T细胞内在无能的证据。人们正在寻求克服这些抑制机制的治疗策略，抗PD-1单抗已经获得FDA的批准。在同一肿瘤微环境中存在多种抑制机制，这表明联合治疗可能是有利的，其中几种正在进行临床测试。在非T细胞浸润性肿瘤微环境中，可能需要一种新的范式来促进从头发炎。对肿瘤的天然天然免疫感应似乎是通过宿主刺痛途径、I型干扰素的产生以及通过CD8CD8α+DC交叉激发T细胞来实现的。正在开发新的策略来治疗这一途径，例如通过刺痛激动剂。调节T细胞炎性肿瘤微环境存在或不存在的分子机制正在利用平行基因组学平台进行阐明。第一个被发现的介导免疫排斥的癌基因途径是Wnt/β-Catenin途径，这表明应该开发针对这一途径的新的药理学策略，以恢复对肿瘤微环境的免疫访问。
Most cancers express tumor antigens that can be recognized by T cells of the host. The fact that cancers become clinically evident nonetheless implies that immune escape must occur. Two major subsets of human melanoma metastases have been identified based on gene expression profiling. One subgroup has a T cell-inflamed phenotype that includes expression of chemokines, T cell markers, and a type I IFN signature. In contrast, the other major subset lacks this phenotype and has been designated as non-T cell-inflamed. The mechanisms of immune escape are likely distinct in these two phenotypes, and therefore the optimal immunotherapeutic interventions necessary to promote clinical responses may be different. The T cell-inflamed tumor microenvironment subset shows the highest expression of negative regulatory factors, including PD-L1, IDO, FoxP3+Tregs, and evidence for T cell-intrinsic anergy. Therapeutic strategies to overcome these inhibitory mechanisms are being pursued, and anti-PD-1 mAbs have been FDA approved. The presence of multiple inhibitory mechanisms in the same tumor microenvironment argues that combination therapies may be advantageous, several of which are in clinical testing. A new paradigm may be needed to promote de novo inflammation in cases of the non-T cell-infiltrated tumor microenvironment. Natural innate immune sensing of tumors appears to occur via the host STING pathway, type I IFN production, and cross-priming of T cells via CD8α+DCs. New strategies are being developed to engage this pathway therapeutically, such as through STING agonists. The molecular mechanisms that mediate the presence or absence of the T cell-inflamed tumor microenvironment are being elucidated using parallel genomics platforms. The first oncogene pathway identified that mediates immune exclusion is the Wnt/β-catenin pathway, suggesting that new pharmacologic strategies to target this pathway should be developed to restore immune access to the tumor microenvironment.
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影响因子：
8.8
作者：
Corrales L;Glickman LH;McWhirter SM;Kanne DB;Sivick KE;Katibah GE;Woo SR;Lemmens E;Banda T;Leong JJ;Metchette K;Dubensky TW Jr;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1084/jem.20101159
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fuertes MB;Kacha AK;Kline J;Woo SR;Kranz DM;Murphy KM;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
11.2
作者：
Burnette BC;Liang H;Lee Y;Chlewicki L;Khodarev NN;Weichselbaum RR;Fu YX;Auh SL
通讯作者：
Auh SL
DOI：
10.1056/nejmoa1312625
发表时间：
2014-08-07
期刊：
The New England journal of medicine
影响因子：
--
作者：
Liu Y;Jesus AA;Marrero B;Yang D;Ramsey SE;Sanchez GAM;Tenbrock K;Wittkowski H;Jones OY;Kuehn HS;Lee CR;DiMattia MA;Cowen EW;Gonzalez B;Palmer I;DiGiovanna JJ;Biancotto A;Kim H;Tsai WL;Trier AM;Huang Y;Stone DL;Hill S;Kim HJ;St Hilaire C;Gurprasad S;Plass N;Chapelle D;Horkayne-Szakaly I;Foell D;Barysenka A;Candotti F;Holland SM;Hughes JD;Mehmet H;Issekutz AC;Raffeld M;McElwee J;Fontana JR;Minniti CP;Moir S;Kastner DL;Gadina M;Steven AC;Wingfield PT;Brooks SR;Rosenzweig SD;Fleisher TA;Deng Z;Boehm M;Paller AS;Goldbach-Mansky R
通讯作者：
Goldbach-Mansky R
影响因子：
11.2
作者：
Harlin H;Meng Y;Peterson AC;Zha Y;Tretiakova M;Slingluff C;McKee M;Gajewski TF
通讯作者：
Gajewski TF