Divergent tumor and immune cell reprogramming underlying immunotherapy response and immune-related adverse events in lung squamous cell carcinoma

被引:16
作者
Chen, Minjiang [1 ]
Ma, Pengfei [2 ]
Zhang, Yongchang [3 ]
Wang, Dong [4 ]
Yu, Zhuang [5 ]
Fu, Yujie [2 ]
Zhao, Xiaojing [2 ]
Wang, Mengzhao [1 ]
Zhuang, Guanglei [2 ,6 ]
Jing, Ying [7 ]
机构
[1] Chinese Acad Med Sci & Peking Union Med Coll, Peking Union Med Coll Hosp, Dept Resp & Crit Care Med, Beijing, Peoples R China
[2] Shanghai Jiao Tong Univ, Ren Ji Hosp, Shanghai Canc Inst, State Key Lab Syst Med Canc,Sch Med,Dept Thorac Su, Shanghai, Peoples R China
[3] Cent South Univ, Lung Canc & Gastrointestinal Unit, Affiliated Canc Hosp, Dept Med Oncol,Hunan Canc Hosp,Xiangya Sch Med, Changsha, Peoples R China
[4] Jiading Dist Anting Hosp Shanghai, Dept Orthopaed, Shanghai, Peoples R China
[5] Qingdao Univ, Dept Oncol, Affiliated Hosp, Qingdao, Peoples R China
[6] Shanghai Jiao Tong Univ, Sch Med, Ren Ji Hosp, Shanghai Key Lab Gynecol Oncol, Shanghai, Peoples R China
[7] Fudan Univ, Ctr Intelligent Med Res, Greater Bay Area Inst Precis Med Guangzhou, Sch Life Sci, Guangzhou, Peoples R China
关键词
Immune Checkpoint Inhibitors; Tumor Microenvironment; Lung Neoplasms; CHECKPOINT INHIBITOR; THERAPIES;
D O I
10.1136/jitc-2023-007305
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
BackgroundLung squamous cell carcinoma (LUSC) remains a leading cause of cancer-related deaths with few therapeutic strategies. Immune checkpoint inhibitors (ICIs) have demonstrated promising efficacy in patients with LUSC. However, ICIs could also lead to a unique spectrum of immune-related adverse events (irAEs), which dampen the clinical outcome. In-depth characterization of the immune hallmarks of antitumor responses and irAEs remains an unmet need to maximize ICI-treatment benefits of patients.MethodsWe performed single-cell RNA sequencing (scRNA-seq) on pre-ICI and on-ICI treatment tumor biopsies. We used bulk RNA-seq data of matched pretreatment/on-treatment tumors and irAE affected organs to validate observations from scRNA-seq analysis. Two independent patient cohorts were collected to determine circulating tumor necrosis factor (TNF) protein expression levels.ResultsWe found that increased proportions of a macrophage subcluster with highly expressed secreted phosphoprotein 1 (SPP1) and two tumor cell subclusters in irAE patients, whereas proportions of two cytotoxic CD8+ T cell subclusters were higher in patients with partial response (PR). TNF signaling pathway was conversely associated with treatment efficacy and irAE development in most macrophage and tumor cell subclusters. Cell-cell communications for TNF ligand-receptor pairs between macrophage/T cells and tumor cells were also bidirectionally remodeled in responders versus non-responders and irAE versus non-irAE patients. Bulk RNA-seq analysis on matched pretreatment/on-treatment tumors and irAE affected organs revealed remarkably enhanced macrophage abundance and TNF signaling pathway in on-treatment tumors and organs developed irAEs. Furthermore, we observed significantly increased circulating TNF protein in plasma or serum of irAE patients but not ICI responders, based on analysis of two independent LUSC patient cohorts and one published ICI patient cohort.ConclusionsOur data depicts specific reprogramming of macrophage, T cells and tumor cells associated with ICI response and irAEs, elucidates divergent roles of TNF signaling in antitumor immunity and irAEs, and highlights the significance of TNF expression in irAE development in the LUSC setting.
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页数:12
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共 40 条
[1]   Signalling pathways of the TNF superfamily: A double-edged sword [J].
Aggarwal, BB .
NATURE REVIEWS IMMUNOLOGY, 2003, 3 (09) :745-756
[2]   Tumour necrosis factor and cancer [J].
Balkwill, Frances .
NATURE REVIEWS CANCER, 2009, 9 (05) :361-371
[3]   Association of Checkpoint Inhibitor-Induced Toxic Effects With Shared Cancer and Tissue Antigens in Non-Small Cell Lung Cancer [J].
Berner, Fiamma ;
Bomze, David ;
Diem, Stefan ;
Ali, Omar Hasan ;
Faessler, Mirjam ;
Ring, Sandra ;
Niederer, Rebekka ;
Ackermann, Christoph J. ;
Baumgaertner, Petra ;
Pikor, Natalia ;
Cruz, Cristina Gil ;
van de Veen, Willem ;
Akdis, Muebeccel ;
Nikolaev, Sergey ;
Laeubli, Heinz ;
Zippelius, Alfred ;
Hartmann, Fabienne ;
Cheng, Hung-Wei ;
Hoenger, Gideon ;
Recher, Mike ;
Goldman, Jonathan ;
Cozzi, Antonio ;
Fruek, Martin ;
Neefjes, Jacques ;
Driessen, Christoph ;
Ludewig, Burkhard ;
Hegazy, Ahmed N. ;
Jochum, Wolfram ;
Speiser, Daniel E. ;
Flatz, Lukas .
JAMA ONCOLOGY, 2019, 5 (07) :1043-1047
[4]   Tumor and immune reprogramming during immunotherapy in advanced renal cell carcinoma [J].
Bi, Kevin ;
He, Meng Xiao ;
Bakouny, Ziad ;
Kanodia, Abhay ;
Napolitano, Sara ;
Wu, Jingyi ;
Grimaldi, Grace ;
Braun, David A. ;
Cuoco, Michael S. ;
Mayorga, Angie ;
DelloStritto, Laura ;
Bouchard, Gabrielle ;
Steinharter, John ;
Tewari, Alok K. ;
Vokes, Natalie, I ;
Shannon, Erin ;
Sun, Maxine ;
Park, Jihye ;
Chang, Steven L. ;
McGregor, Bradley A. ;
Haq, Rizwan ;
Denize, Thomas ;
Signoretti, Sabina ;
Guerriero, Jennifer L. ;
Vigneau, Sebastien ;
Rozenblatt-Rosen, Orit ;
Rotem, Asaf ;
Regev, Aviv ;
Choueiri, Toni K. ;
Van Allen, Eliezer M. .
CANCER CELL, 2021, 39 (05) :649-+
[5]   Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers (vol 596, pg 126, 2021) [J].
Caushi, Justina X. ;
Zhang, Jiajia ;
Ji, Zhicheng ;
Vaghasia, Ajay ;
Zhang, Boyang ;
Hsiue, Emily Han-Chung ;
Mog, Brian J. ;
Hou, Wenpin ;
Justesen, Sune ;
Blosser, Richard ;
Tam, Ada ;
Anagnostou, Valsamo ;
Cottrell, Tricia R. ;
Guo, Haidan ;
Chan, Hok Yee ;
Singh, Dipika ;
Thapa, Sampriti ;
Dykema, Arbor G. ;
Burman, Poromendro ;
Choudhury, Begum ;
Aparicio, Luis ;
Cheung, Laurene S. ;
Lanis, Mara ;
Belcaid, Zineb ;
El Asmar, Margueritta ;
Illei, Peter B. ;
Wang, Rulin ;
Meyers, Jennifer ;
Schuebel, Kornel ;
Gupta, Anuj ;
Skaist, Alyza ;
Wheelan, Sarah ;
Naidoo, Jarushka ;
Marrone, Kristen A. ;
Brock, Malcolm ;
Ha, Jinny ;
Bush, Errol L. ;
Park, Bernard J. ;
Bott, Matthew ;
Jones, David R. ;
Reuss, Joshua E. ;
Velculescu, Victor E. ;
Chaft, Jamie E. ;
Kinzler, Kenneth W. ;
Zhou, Shibin ;
Vogelstein, Bert ;
Taube, Janis M. ;
Hellmann, Matthew D. ;
Brahmer, Julie R. ;
Merghoub, Taha .
NATURE, 2021, 598 (7881) :E1-E1
[6]   A pan-cancer single-cell transcriptional atlas of tumor infiltrating myeloid cells [J].
Cheng, Sijin ;
Li, Ziyi ;
Gao, Ranran ;
Xing, Baocai ;
Gao, Yunong ;
Yang, Yu ;
Qin, Shishang ;
Zhang, Lei ;
Ouyang, Hanqiang ;
Du, Peng ;
Jiang, Liang ;
Zhang, Bin ;
Yang, Yue ;
Wang, Xiliang ;
Ren, Xianwen ;
Bei, Jin-Xin ;
Hu, Xueda ;
Bu, Zhaode ;
Ji, Jiafu ;
Zhang, Zemin .
CELL, 2021, 184 (03) :792-+
[7]   Uncoupling immune trajectories of response and adverse events from anti-PD-1 immunotherapy in hepatocellular carcinoma [J].
Chuah, Samuel ;
Lee, Joycelyn ;
Song, Yuan ;
Kim, Hyung-Don ;
Wasser, Martin ;
Kaya, Neslihan A. ;
Bang, Kyunghye ;
Lee, Yong Joon ;
Jeon, Seung Hyuck ;
Suthen, Sheena ;
A'Azman, Shamirah ;
Gien, Gerald ;
Lim, Chun Jye ;
Chua, Camillus ;
Hazirah, Sharifah Nur ;
Lee, Hong Kai ;
Lim, Jia Qi ;
Lim, Tony K. H. ;
Yeong, Joe ;
Chen, Jinmiao ;
Shin, Eui-Cheol ;
Albani, Salvatore ;
Zhai, Weiwei ;
Yoo, Changhoon ;
Liu, Haiyan ;
Choo, Su Pin ;
Tai, David ;
Chew, Valerie .
JOURNAL OF HEPATOLOGY, 2022, 77 (03) :683-694
[8]   Evaluating T-cell cross-reactivity between tumors and immune-related adverse events with TCR sequencing: pitfalls in interpretations of functional relevance [J].
Cottrell, Tricia ;
Zhang, Jiajia ;
Zhang, Boyang ;
Kaunitz, Genevieve J. ;
Burman, Poromendro ;
Chan, Hok-Yee ;
Verde, Franco ;
Hooper, Jody E. ;
Hammers, Hans ;
Allaf, Mohamad E. ;
Ji, Hongkai ;
Taube, Janis ;
Smith, Kellie N. .
JOURNAL FOR IMMUNOTHERAPY OF CANCER, 2021, 9 (07)
[9]   Nivolumab Plus Ipilimumab vs Nivolumab for Previously Treated Patients With Stage IV Squamous Cell Lung Cancer The Lung-MAP S1400I Phase 3 Randomized Clinical Trial [J].
Gettinger, Scott N. ;
Redman, Mary W. ;
Bazhenova, Lyudmila ;
Hirsch, Fred R. ;
Mack, Philip C. ;
Schwartz, Lawrence H. ;
Bradley, Jeffrey D. ;
Stinchcombe, Thomas E. ;
Leighl, Natasha B. ;
Ramalingam, Suresh S. ;
Tavernier, Susan S. ;
Yu, Hui ;
Unger, Joseph M. ;
Minichiello, Katherine ;
Highleyman, Louise ;
Papadimitrakopoulou, Vassiliki A. ;
Kelly, Karen ;
Gandara, David R. ;
Herbst, Roy S. .
JAMA ONCOLOGY, 2021, 7 (09) :1368-1377
[10]   Applying high-dimensional single-cell technologies to the analysis of cancer immunotherapy [J].
Gohil, Satyen H. ;
Iorgulescu, J. Bryan ;
Braun, David A. ;
Keskin, Derin B. ;
Livak, Kenneth J. .
NATURE REVIEWS CLINICAL ONCOLOGY, 2021, 18 (04) :244-256