Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma

doi:10.1136/jitc-2020-000807

	Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma
	He, Xiran 1,2; Du, Yang2,3 ; Wang, Zhijie 1; Wang, Xin 1; Duan, Jianchun 1; Wan, Rui 1; Xu, Jiachen 1; Zhang, Pei 1,2; Wang, Di1,2 ; Tian, Yanhua 4; Han, Jiefei 1; Fei, Kailun 1; Bai, Hua 1; Tian, Jie 2,5; Wang, Jie 1
发表期刊	JOURNAL FOR IMMUNOTHERAPY OF CANCER
	2020
卷号	8 期号:2 页码:15
通讯作者	Bai, Hua(baihuahb@sina.com) ; Tian, Jie(jie.tian@ia.ac.cn) ; Wang, Jie(zlhuxi@163.com)
摘要	Background The survival benefits of combining chemotherapy (at the maximum tolerated dose, MTD) with concurrent immunotherapy, collectively referred to as chemoimmunotherapy, for the treatment of squamous cell lung carcinoma (SQCLC) have been confirmed in recent clinical trials. Nevertheless, optimization of chemoimmunotherapy in order to enhance the efficacy of immune checkpoint inhibitors (ICIs) in SQCLC remains to be explored. Methods Cell lines, syngeneic immunocompetent mouse models, and patients' peripheral blood mononuclear cells were used in order to comprehensively explore how to enhance ectopic lymphoid-like structures (ELSs) and upregulate the therapeutic targets of anti-programmed death 1 (PD-1)/anti-PD-1 ligand (PD-L1) monoclonal antibodies (mAbs), thus rendering SQCLC more sensitive to ICIs. In addition, molecular mechanisms underlying optimization were characterized. Results Low-dose chemotherapy contributed to an enhanced antigen exposure via the phosphatidylinositol 3-kinase/Akt/transcription factor nuclear factor kappa B signaling pathway. Improved antigen uptake and presentation by activated dendritic cells (DCs) was observed, thus invoking specific T cell responses leading to systemic immune responses and immunological memory. In turn, enhanced antitumor ELSs and PD-1/PD-L1 expression was observed in vivo. Moreover, upfront metronomic (low-dose and frequent administration) chemotherapy extended the time window of the immunostimulatory effect and effectively synergized with anti-PD-1/PD-L1 mAbs. A possible mechanism underlying this synergy is the increase of activated type I macrophages, DCs, and cytotoxic CD8(+) T cells, as well as the maintenance of intestinal gut microbiota diversity and composition. In contrast, when combining routine MTD chemotherapy with ICIs, the effects appeared to be additive rather than synergistic. Conclusions We first attempted to optimize chemoimmunotherapy for SQCLC by investigating different combinatorial modes. Compared with the MTD chemotherapy used in current clinical practice, upfront metronomic chemotherapy performed better with subsequent anti-PD-1/PD-L1 mAb treatment. This combination approach is worth investigating in other types of tumors, followed by translation into the clinic in the future.
关键词	drug therapy combination immunotherapy lung neoplasms lymphocytes tumor-infiltrating translational medical research
DOI	10.1136/jitc-2020-000807
关键词[WOS]	IMMUNE CHECKPOINT INHIBITORS ; 2ND-LINE TREATMENT ; CANCER ; THERAPY ; IMMUNOMODULATION ; INFLAMMATION ; COMBINATION ; MICROBIOTA ; CISPLATIN ; REGIMENS
收录类别	SCI
语种	英语
资助项目	Ministry of Science and Technology of China[2017YFA0205] ; Ministry of Education Innovation Team Development Project[IRT-17R10] ; National Natural Science Foundation of China[81871514] ; National Natural Science Foundation of China[81227901] ; National Natural Science Foundation of China[81470083] ; National Natural Science Foundation of China[91859119] ; National Natural Sciences Foundation Key Program[81630071] ; National Key Research and Development Project[2019YFC1315700] ; CAMS Innovation Fund for Medical Sciences[CIFMS 2016-I2M-3-008] ; CAMS Key Lab of Translational Research on Lung Cancer[2018PT31035] ; Aiyou Foundation[KY201701]
项目资助者	Ministry of Science and Technology of China ; Ministry of Education Innovation Team Development Project ; National Natural Science Foundation of China ; National Natural Sciences Foundation Key Program ; National Key Research and Development Project ; CAMS Innovation Fund for Medical Sciences ; CAMS Key Lab of Translational Research on Lung Cancer ; Aiyou Foundation
WOS研究方向	Oncology ; Immunology
WOS类目	Oncology ; Immunology
WOS记录号	WOS:000587927100006
出版者	BMJ PUBLISHING GROUP
七大方向——子方向分类	其他
引用统计	被引频次：31[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://ir.ia.ac.cn/handle/173211/41735
专题	中国科学院分子影像重点实验室
通讯作者	Bai, Hua; Tian, Jie; Wang, Jie
作者单位	1.Chinese Acad Med Sci & Peking Union Med Coll, Natl Clin Res Ctr Canc, Canc Hosp, Dept Med Oncol,Natl Canc Ctr, Beijing, Peoples R China 2.Univ Chinese Acad Sci, Inst Automat, State Key Lab Management & Control Complex Syst, CAS Key Lab Mol Imaging, Beijing, Peoples R China 3.Univ Chinese Acad Sci, Beijing, Peoples R China 4.UT MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX USA 5.Beihang Univ, Beijing Adv Innovat Ctr Big Data Based Precis Med, Sch Med, Beijing, Peoples R China
第一作者单位	中国科学院自动化研究所
通讯作者单位	中国科学院自动化研究所
推荐引用方式 GB/T 7714	He, Xiran,Du, Yang,Wang, Zhijie,et al. Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma[J]. JOURNAL FOR IMMUNOTHERAPY OF CANCER,2020,8(2):15.
APA	He, Xiran.,Du, Yang.,Wang, Zhijie.,Wang, Xin.,Duan, Jianchun.,...&Wang, Jie.(2020).Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma.JOURNAL FOR IMMUNOTHERAPY OF CANCER,8(2),15.
MLA	He, Xiran,et al."Upfront dose-reduced chemotherapy synergizes with immunotherapy to optimize chemoimmunotherapy in squamous cell lung carcinoma".JOURNAL FOR IMMUNOTHERAPY OF CANCER 8.2(2020):15.