CXCR6 is required for antitumor efficacy of intratumoral CD8(+) T cell.
CXCR6 is required for antitumor efficacy of intratumoral CD8(+) T cell.
复制标题
CXCR6 是肿瘤内 CD8 T 细胞抗肿瘤功效所必需的
DOI：
10.1136/jitc-2021-003100
复制
发表时间：
2021-08
影响因子：
10.9
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Wang B;Wang Y;Sun X;Deng G;Huang W;Wu X;Gu Y;Tian Z;Fan Z;Xu Q;Chen H;Sun Y
肿瘤组织中CD 8 + T细胞浸润的增加预示着更好的预后，并且对于对检查点阻断治疗的反应至关重要。此外，目前的临床方案使用未分级的T细胞群体作为嵌合抗原受体（汽车）修饰的T细胞转导的起点，但CAR修饰的T细胞的最佳T细胞亚型仍不清楚。因此，准确鉴定一组具有高抗肿瘤功效的细胞毒性T淋巴细胞是必要的。受阴阳学说的启发，我们探索了癌症中的CD 8 + T细胞亚群，其表型特征与自身免疫性疾病中高度活化的炎性T细胞相同。单细胞RNA测序、通用转录组测序数据和多参数细胞计数技术的组合使我们能够绘制特定细胞类型和组织上的CXCR 6表达。我们应用Cxcr 6 −/−小鼠、免疫检查点疗法和骨髓嵌合体来鉴定CXCR 6 + CD 8 + T细胞的功能。采用转基因Cxcr 6 −/− OT-I小鼠来探索CXCR 6在抗原特异性抗肿瘤反应中的功能作用。我们发现CXCR 6只表达于肿瘤内的CD 8 + T细胞。CXCR 6 + CD 8 + T细胞具有更强的免疫活性，而CD 8 + T细胞特异性缺陷的嵌合体显示出较弱的抗肿瘤活性。此外，Cxcr 6 −/−小鼠不能有效地对抗PD-1治疗作出反应。CXCR 6在肿瘤组织中的高表达主要不是由CXCL 16/CXCR 6的配体-受体趋化作用引起的，而是由肿瘤组织自身诱导的。诱导的CXCR 6 + CD 8 + T细胞具有肿瘤抗原特异性，可以增强抗PD-1阻断剂的作用，延缓肿瘤进展。本研究为联合免疫治疗的合理设计提供了理论依据。或者，CXCR 6可作为过继性细胞治疗前有效CD 8 + T细胞状态的生物标志物，为肿瘤免疫治疗提供基础。
Increasing infiltration of CD8+ T cells within tumor tissue predicts a better prognosis and is essential for response to checkpoint blocking therapy. Furthermore, current clinical protocols use unfractioned T cell populations as the starting point for transduction of chimeric antigen receptors (CARs)-modified T cells, but the optimal T cell subtype of CAR-modified T cells remains unclear. Thus, accurately identifying a group of cytotoxic T lymphocytes with high antitumor efficacy is imperative. Inspired by the theory of yin and yang, we explored a subset of CD8+ T cell in cancer with the same phenotypic characteristics as highly activated inflammatory T cells in autoimmune diseases. Combination of single-cell RNA sequencing, general transcriptome sequencing data and multiparametric cytometric techniques allowed us to map CXCR6 expression on specific cell type and tissue. We applied Cxcr6−/− mice, immune checkpoint therapies and bone marrow chimeras to identify the function of CXCR6+CD8+ T cells. Transgenic Cxcr6−/− OT-I mice were employed to explore the functional role of CXCR6 in antigen-specific antitumor response. We identified that CXCR6 was exclusively expressed on intratumoral CD8+ T cell. CXCR6+CD8+ T cells were more immunocompetent, and chimeras with specific deficiency on CD8+ T cells showed weaker antitumor activity. In addition, Cxcr6−/− mice could not respond to anti-PD-1 treatment effectively. High tumor expression of CXCR6 was not mainly caused by ligand-receptor chemotaxis of CXCL16/CXCR6 but induced by tumor tissue self. Induced CXCR6+CD8+ T cells possessed tumor antigen specificity and could enhance the effect of anti-PD-1 blockade to retard tumor progression. This study may contribute to the rational design of combined immunotherapy. Alternatively, CXCR6 may be used as a biomarker for effective CD8+ T cell state before adoptive cell therapy, providing a basis for tumor immunotherapy.
登录
查看更多内容
DOI：
10.1084/jem.20092454
发表时间：
2010-08-02
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Thompson ED;Enriquez HL;Fu YX;Engelhard VH
通讯作者：
Engelhard VH
影响因子：
20.3
作者：
Kochenderfer, James N.;Wilson, Wyndham H.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
影响因子：
5.6
作者：
Korbecki J;Bajdak-Rusinek K;Kupnicka P;Kapczuk P;Simińska D;Chlubek D;Baranowska-Bosiacka I
通讯作者：
Baranowska-Bosiacka I
影响因子：
50.3
作者：
Srivastava S;Furlan SN;Jaeger-Ruckstuhl CA;Sarvothama M;Berger C;Smythe KS;Garrison SM;Specht JM;Lee SM;Amezquita RA;Voillet V;Muhunthan V;Yechan-Gunja S;Pillai SPS;Rader C;Houghton AM;Pierce RH;Gottardo R;Maloney DG;Riddell SR
通讯作者：
Riddell SR
影响因子：
64.8
作者：
JOHNSTON, JA;KAWAMURA, M;O'SHEA, JJ
通讯作者：
O'SHEA, JJ