2. Academic Validation
  3. Angiotensin receptor blocker attacks armored and cold tumors and boosts immune checkpoint blockade

Angiotensin receptor blocker attacks armored and cold tumors and boosts immune checkpoint blockade

  • J Immunother Cancer. 2024 Sep 6;12(9):e009327. doi: 10.1136/jitc-2024-009327.
Jie Mei # 1 2,  Jiahui Chu # 1 2,  Kai Yang # 1 2,  Zhiwen Luo # 3,  Jiayue Yang 4,  Junying Xu 5,  Qing Li 6,  Yan Zhang 7 8,  Qinglin Zhang 9,  Mengyun Wan 10,  Ningyi Xue 2 11,  Junli Ding 12,  Yichao Zhu 13,  Yun Cai 14,  Yongmei Yin 15 16
Affiliations

Affiliations

  • 1 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • 2 The First Clinical Medicine College, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 3 Department of Sports Medicine, Huashan Hospital Affiliated to Fudan University, Shanghai, China.
  • 4 Departments of Endocrinology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, China.
  • 5 Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, China.
  • 6 Departments of Oncology, Xuzhou Central Hospital, The Xuzhou School of Clinical Medicine of Nanjing Medical University, Xuzhou, Jiangsu, China.
  • 7 Departments of Gynecology, The Obstetrics and Gynecology Hospital Affiliated to Jiangnan University, Wuxi, Jiangsu, China.
  • 8 Departments of Gynecology, Wuxi Maternal and Child Health Care Hospital, Nanjing Medical University, Wuxi, Jiangsu, China.
  • 9 Departments of Gastroenterology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, China.
  • 10 Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China.
  • 11 Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
  • 12 Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi Medical Center, Nanjing Medical University, Wuxi, Jiangsu, China ymyin@njmu.edu.cn kellie_cai@163.com zhuyichao@njmu.edu.cn dingjunliletters@163.com.
  • 13 Department of Physiology, School of Basic Medical Sciences, Nanjing Medical University, Nanjing, Jiangsu, China ymyin@njmu.edu.cn kellie_cai@163.com zhuyichao@njmu.edu.cn dingjunliletters@163.com.
  • 14 Department of Central Laboratory, The First People's Hospital of Jintan, Jintan Affiliated Hospital of Jiangsu University, Changzhou, Jiangsu, China ymyin@njmu.edu.cn kellie_cai@163.com zhuyichao@njmu.edu.cn dingjunliletters@163.com.
  • 15 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China ymyin@njmu.edu.cn kellie_cai@163.com zhuyichao@njmu.edu.cn dingjunliletters@163.com.
  • 16 Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, Jiangsu, China.
  • # Contributed equally.
PMID: 39244215 DOI: 10.1136/jitc-2024-009327
Abstract

Background: Immune checkpoint blockade (ICB) has made remarkable achievements, but newly identified armored and cold tumors cannot respond to ICB therapy. The high prevalence of concomitant medications has huge impact on immunotherapeutic responses, but the clinical effects on the therapeutic outcome of armored and cold tumors are still unclear.

Methods: In this research, using large-scale transcriptomics datasets, the expression and potential biological functions of angiotensin II receptor 1 (AGTR1), the target of Angiotensin Receptor blocker (ARB), were investigated. Next, the roles of ARB in tumor cells and tumor microenvironment cells were defined by a series of in vitro and in vivo assays. In addition, the clinical impacts of ARB on ICB therapy were assessed by multicenter cohorts and meta-analysis.

Results: AGTR1 was overexpressed in armored and cold tumors and associated with poor response to ICB therapy. ARB, the inhibitor for AGTR1, only suppressed the aggressiveness of tumor cells with high AGTR1 expression, which accounted for a very small proportion. Further analysis revealed that AGTR1 was always highly expressed in cancer-associated fibroblasts (CAFs) and ARB inhibited type I collagen expression in CAFs by suppressing the RhoA-YAP axis. Moreover, ARB could also drastically reverse the phenotype of armored and cold to soft and hot in vivo, leading to a higher response to ICB therapy. In addition, both our in-house cohorts and meta-analysis further supported the idea that ARB can significantly enhance ICB efficacy.

Conclusion: Overall, we identify AGTR1 as a novel target in armored and cold tumors and demonstrate the improved therapeutic efficacy of ICB in combination with ARB. These findings could provide novel clinical insight into how to treat patients with refractory armored and cold tumors.

Keywords

Immunotherapy; Tumor Microenvironment.

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