TGFBR2 mutation predicts resistance to immune checkpoint inhibitors in patients with non-small cell lung cancer

Teng Li; Han Wang; Jiachen Xu; Chengcheng Li; Yudong Zhang; Guoqiang Wang; Yutao Liu; Shangli Cai; Wenfeng Fang; Junling Li; Zhijie Wang

doi:10.1177/17588359211038477

TGFBR2 mutation predicts resistance to immune checkpoint inhibitors in patients with non-small cell lung cancer

Ther Adv Med Oncol. 2021 Aug 14:13:17588359211038477. doi: 10.1177/17588359211038477. eCollection 2021.

Authors

Teng Li¹, Han Wang², Jiachen Xu³, Chengcheng Li⁴, Yudong Zhang⁵, Guoqiang Wang⁴, Yutao Liu¹, Shangli Cai⁴, Wenfeng Fang⁶, Junling Li⁷, Zhijie Wang⁷

Affiliations

¹ Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
² School of Mathematical Sciences and Center for Statistical Science, Peking University, Beijing, China.
³ State Key Laboratory of Molecular Oncology, Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
⁴ Burning Rock Biotech, Guangzhou, China.
⁵ Affiliated hospital of Nantong University, Jiangsu, China.
⁶ State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China.
⁷ Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 17 Pan-jia-yuan South Lane, Chaoyang District, Beijing, 100021, China.

Abstract

Background: Resistance or even hyper-progression to immune checkpoint inhibitors (ICIs) manifesting as accelerated disease progression or death has impeded the clinical use of ICIs. The transforming growth factor beta (TGFβ) receptor pathway has been identified in contributing to immune dysfunction, which might be associated with resistance to ICIs. We aimed to explore the role of TGFβ in the resistance to ICIs in non-small cell lung cancer (NSCLC) in this study.

Methods: Public cohorts with patients treated with ICIs or chemotherapy including POPLAR/OAK (n = 853), MSKCC (n = 1662) and Van Allen (n = 57) and TCGA (n = 3210) cohorts were obtained and analyzed.

Results: The expression of immune-checkpoint related genes, including programmed death-ligand 1 (CD274), lymphocyte-activation gene 3 (LAG3), T cell immunoreceptor with Ig and ITIM domains (TIGIT), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death ligand 1 (PDCD1), and programmed cell death 1 ligand 2 (PDCD1LG2) were significantly upregulated in transforming growth factor beta TGFβ receptor 2 (TGFβR2)-mutated patients than those with wild-type TGFBR2 (p < 0.05). In the POPLAR/OAK cohort, TGFBR2-mutated patients showed shorter progression-free survival (PFS) [ p = 0.004; hazard ratio (HR), 2.83; 95% confidence interval (CI), 1.34-6.00] and overall survival (OS) ( p = 0.0006; HR, 3.46; 95% CI, 1.63-7.35) than those with wild-type TGFBR2 when treated with ICIs but not chemotherapy. In the merged MSKCC and Van Allen cohorts, a similar result was observed that the OS was inferior in patients with mutated TGFBR2 compared with those with wild-type TGFBR2 (p = 0.007; HR, 2.53; 95% CI, 1.25-5.12). The association between TGBFR2 mutation and survival remained significant in multivariable cox regression in both POPLAR/OAK cohort (p = 0.02; HR, 2.53; 95% CI, 1.17-5.45) and merged cohort (p = 0.008; HR, 2.63; 95% CI, 1.29-5.35). We further evaluated the association between TGFBR2 mutations and OS in multiple types of tumors. The association between TGFBR2 mutations and OS remained significant in NSCLC (p = 0.02; HR, 2.47; 95% CI, 1.16-5.26), but not in other type of tumors.

Conclusions: We identified that TGFBR2 mutation predicted the resistance to ICIs in NSCLCs. The clinical delivery of ICIs should be cautious in those patients.

Keywords: TGFBR2; immune checkpoint inhibitors; immune resistant; non-small cell lung cancer.