T proliferating cells derived autophagy signature associated with prognosis and immunotherapy resistance in a pan-cancer analysis

Zhongqi Fan; Yutao Liu; Chengcheng Li; Yanfang Jiang; Nanya Wang; Mingda Wang; Chao Li; Yongkang Diao; Wei Qiu; Xin Zhu; Guoqiang Wang; Shangli Cai; Tian Yang; Guoyue Lv

doi:10.1016/j.isci.2023.108701

T proliferating cells derived autophagy signature associated with prognosis and immunotherapy resistance in a pan-cancer analysis

iScience. 2023 Dec 8;27(1):108701. doi: 10.1016/j.isci.2023.108701. eCollection 2024 Jan 19.

Authors

Zhongqi Fan¹, Yutao Liu², Chengcheng Li³, Yanfang Jiang⁴, Nanya Wang⁵, Mingda Wang⁶, Chao Li⁶, Yongkang Diao⁶, Wei Qiu¹, Xin Zhu³, Guoqiang Wang³, Shangli Cai³, Tian Yang^{1

6}, Guoyue Lv¹

Affiliations

¹ Department of Hepatobiliary and Pancreatic Surgery, General Surgery Center, First Hospital of Jilin University, Jilin, China.
² 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.
³ Burning Rock Biotech, Guangdong, China.
⁴ Key Laboratory of Organ Regeneration and Transplantation of the Ministry of Education, Genetic Diagnosis Centre, The First Hospital of Jilin University, Changchun, Jilin, China.
⁵ Phase I Clinical Trial Unit, First Hospital of Jilin University, Jilin, China.
⁶ Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Navy Medical University), Shanghai, China.

Abstract

Despite autophagy modulating tumor immunity in the tumor microenvironment (TME), the immunotherapeutic efficacy and potential mechanism of autophagy signature was not explicit. We manually curated an autophagy gene set and defined a pan-cancer autophagy signature by comparing malignant tissues and normal tissues in The Cancer Genome Atlas (TCGA) cohort. The pan-cancer autophagy signature was derived from T proliferating cells as demonstrated in multiple single-cell RNA sequencing (scRNA-seq) datasets. The pan-cancer autophagy signature could influence the cell-cell interactions in the TME and predict the responsiveness of immune checkpoint inhibitors (ICIs) in the metastatic renal cell carcinoma, non-small cell lung cancer, bladder cancer, and melanoma cohorts. Metabolism inactivation accompanied with dysregulation of autophagy was investigated with transcriptomic and proteomic data. The immunotherapeutic predictive role and mechanism regulation of the autophagy signature was validated in an in-house cohort. Our study provides valuable insights into the mechanisms of ICI resistance.

Keywords: Cancer; Immunology; Molecular genetics.