Research Paper|Volume 15, Issue 23|pp 14333—14371

Single-cell dissection reveals the role of aggrephagy patterns in tumor microenvironment components aiding predicting prognosis and immunotherapy on lung adenocarcinoma

Xinti Sun¹, Fei Meng¹, Minyu Nong², Hao Fang¹, Chenglu Lu³, Yan Wang¹, Peng Zhang¹

¹Department of Cardiothoracic Surgery, Tianjin Medical University General Hospital, Tianjin 300052, China
²School of Clinical Medicine, Youjiang Medical University for Nationalities, Baise, Guangxi, China
³Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

* Equal contribution

Received: July 17, 2023Accepted: November 6, 2023Published: December 13, 2023

https://doi.org/10.18632/aging.205306

Copyright: © 2023 Sun et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Background: Lung adenocarcinoma (LUAD) is one of the leading malignant cancers. Aggrephagy plays a critical role in key genetic events for various cancers; yet, how aggrephagy functions within the tumor microenvironment (TME) in LUAD remains to be elucidated.

Methods: In this study, by sequential non-negative matrix factorization (NMF) algorithm, pseudotime analysis, cell-cell interaction analysis, and SCENIC analysis, we have shown that aggrephagy genes demonstrated various patterns among different cell types in LUAD TME. LUAD and Immunotherapy cohorts from public repository were used to determine the prognosis and immune response of aggrephagy TME subtypes. The aggrephagy-deprived prognostic score (ADPS) was quantified based on machine learning algorithms.

Results: The cancer-associated fibroblasts (CAFs), tumor-associated macrophages (TAMs), and CD8+ T cells have various aggrephagy patterns, which enhance the intensity of intercellular communication and transcription factor activation. Furthermore, based on the signatures of the newly defined aggrephagy cell subtypes and expression profiles of large cohorts in LUAD patients, we determine that DYNC1I2+CAF-C1, DYNLL1+CAF-C2, PARK7+CAF-C3, VIM+Mac-C1, PARK7+Mac-C2, VIM+CD8+T_cells-C1, UBA52+CD8+T_cells-C2, TUBA4A+CD8+T_ cells-C3, and TUBA1A+CD8+T_cells-C4 are crucial prognostic factors for LUAD patients. The developed ADPS could predict survival outcomes and immunotherapeutic response across ten cohorts (n = 1838), and patients with low ADPS owned a better prognosis, lower genomic alterations, and are more sensitive to immunotherapy. Meanwhile, based on PRISM, CTRP, and CMAP databases, PLK inhibitor BI-2536, may be a potential agent for patients with high ADPS.

Conclusions: Taken together, our novel and systematic single-cell analysis has revealed the unique role of aggrephagy in remodeling the TME of LUAD. As a newly demonstrated biomarker, the ADPS facilitates the clinical management and individualized treatment of LUAD.