2. Academic Validation
  3. Nasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70-CD27 interaction

Nasopharyngeal carcinoma cells promote regulatory T cell development and suppressive activity via CD70-CD27 interaction

  • Nat Commun. 2023 Apr 6;14(1):1912. doi: 10.1038/s41467-023-37614-6.
Lanqi Gong # 1 2,  Jie Luo # 1,  Yu Zhang # 3 4 5,  Yuma Yang 1,  Shanshan Li 2,  Xiaona Fang 1,  Baifeng Zhang 1,  Jiao Huang 1,  Larry Ka-Yue Chow 1,  Dittman Chung 1,  Jinlin Huang 1,  Cuicui Huang 1 2,  Qin Liu 1 2,  Lu Bai 1 2,  Yuen Chak Tiu 1,  Pingan Wu 6,  Yan Wang 7,  George Sai-Wah Tsao 8,  Dora Lai-Wan Kwong 1 2,  Anne Wing-Mui Lee 1 2 9,  Wei Dai 1 2,  Xin-Yuan Guan 10 11 12 13 14
Affiliations

Affiliations

  • 1 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 2 Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
  • 3 Department of Pediatric Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 4 State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 5 Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China.
  • 6 Department of Surgery, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
  • 7 Department of Pathology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.
  • 8 School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
  • 9 Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, China.
  • 10 Department of Clinical Oncology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China. xyguan@hku.hk.
  • 11 Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China. xyguan@hku.hk.
  • 12 State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, China. xyguan@hku.hk.
  • 13 Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China. xyguan@hku.hk.
  • 14 Advanced Energy Science and Technology Guangdong Laboratory, Huizhou, China. xyguan@hku.hk.
  • # Contributed equally.
PMID: 37024479 DOI: 10.1038/s41467-023-37614-6
Abstract

Despite the intense CD8+ T-cell infiltration in the tumor microenvironment of nasopharyngeal carcinoma, anti-PD-1 immunotherapy shows an unsatisfactory response rate in clinical trials, hindered by immunosuppressive signals. To understand how microenvironmental characteristics alter immune homeostasis and limit immunotherapy efficacy in nasopharyngeal carcinoma, here we establish a multi-center single-cell cohort based on public data, containing 357,206 cells from 50 patient samples. We reveal that nasopharyngeal carcinoma cells enhance development and suppressive activity of regulatory T cells via CD70-CD27 interaction. CD70 blocking reverts Treg-mediated suppression and thus reinvigorate CD8+ T-cell immunity. Anti-CD70+ anti-PD-1 therapy is evaluated in xenograft-derived organoids and humanized mice, exhibiting an improved tumor-killing efficacy. Mechanistically, CD70 knockout inhibits a collective lipid signaling network in CD4+ naïve and regulatory T cells involving mitochondrial integrity, Cholesterol homeostasis, and fatty acid metabolism. Furthermore, ATAC-Seq delineates that CD70 is transcriptionally upregulated by NFKB2 via an Epstein-Barr virus-dependent epigenetic modification. Our findings identify CD70+ nasopharyngeal carcinoma cells as a metabolic switch that enforces the lipid-driven development, functional specialization and homeostasis of Tregs, leading to immune evasion. This study also demonstrates that CD70 blockade can act synergistically with anti-PD-1 treatment to reinvigorate T-cell immunity against nasopharyngeal carcinoma.

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