The role of TGF-β pathway alterations in immune regulation as a potential pan-cancer biomarker in immunotherapy

Yan Liang; Wei Li; Bing Qian; Jie Ming; Zhengyi Zhao; Zhengqing Yan; Xiaochen Zhao; Shiqing Chen; Yongmei Yin

doi:10.21037/atm-21-5138

The role of TGF-β pathway alterations in immune regulation as a potential pan-cancer biomarker in immunotherapy

Ann Transl Med. 2021 Nov;9(22):1660. doi: 10.21037/atm-21-5138.

Authors

Yan Liang^#¹, Wei Li^#¹, Bing Qian², Jie Ming³, Zhengyi Zhao⁴, Zhengqing Yan⁴, Xiaochen Zhao⁴, Shiqing Chen⁴, Yongmei Yin^{1

5}

Affiliations

¹ Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
² Nanjing Medical University Affiliated Cancer Hospital Jiangsu Cancer Hospital, Jiangsu Cancer Institute, Nanjing, China.
³ The Affiliated Hospital of Qingdao University, Qingdao, China.
⁴ The Medical Department, 3D Medicines Inc., Shanghai, China.
⁵ Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Medicine, Nanjing Medical University, Nanjing, China.

^# Contributed equally.

Abstract

Background: Depending on the context, the transforming growth factor beta (TGF-β) signaling pathway is involved in opposing cell processes of tumor suppression and tumor promotion. However, the effects of TGF-β pathway on immunotherapy efficacy have not yet been systematically investigated.

Methods: In this study, we have extracted the available data of whole-exome sequencing, messenger RNA (mRNA) expression, baseline characterization, and prognosis information of 10,912 pan-cancer patients from The Cancer Genome Atlas to explore the role of TGF-β pathway in immune regulation. Formalin-fixed, paraffin-embedded tissue samples from 6,717 Chinese cancer patients assayed by next-generation sequencing (NGS) were used as a validation cohort (3DMed cohort). Data sets from the public MSK (Memorial Sloan Kettering Cancer Center) cohort (N=1,610) were used to explore the association of TGF-β pathway with immunotherapy effects.

Results: The results showed that TGF-β pathway alteration was significantly correlated with high microsatellite instability (MSI), high tumor mutational burden, and high neoantigen burden (TNB) (P<0.001 for each). Consistently, the pathway mutations were associated with distinct patterns of immune-related gene expression and tumor-infiltrating immune cells. Patients with TGF-β pathway mutations exhibited significantly worse prognosis than did the wild-type patients regardless of the interventions [overall survival (OS): hazard ratio (HR) 1.20; 95% confidence interval (CI): 1.08-1.33; P=0.001]. However, when treated with immune checkpoint inhibitors (ICIs), superior survival benefit was observed in patients from the mutation group versus the wild-type group (OS: HR 0.73; 95% CI: 0.61-0.88; P=0.001).

Conclusions: Collectively, our study suggested that mutations in TGF-β pathway may be associated with positive immune regulation and better efficacy of immunotherapy.

Keywords: Next-generation sequencing (NGS); immune regulation; microsatellite instability (MSI); solid tumors.