Cancer cachexia-related monocytic myeloid-derived suppressor cells impair T-cell negative selection and predict immune-related adverse events

Abstract

Background and aims: Cancer cachexia is prevalent in various cancers and is associated with chemotherapy toxicity. However, limited data exist on the relationship between cachexia and immune-related adverse events (irAEs). The aim of this study is to explore the correlation between cancer cachexia and irAEs and its possible mechanism.

Methods: A murine model of orthotopic hepatocellular carcinoma (HCC) with cachexia was developed to evaluate the impact of T-cell infiltration into multiple tumor-free organs on the occurrence of irAEs. Single-cell RNA sequencing of thymic stromal cells was performed. Additionally, patients with advanced cancers receiving anti-programmed cell death protein 1/ligand 1 (PD-1/L1) antibody treatment were followed to investigate the relationship between cachexia and irAEs.

Results: Inflammatory cell infiltration was observed in multiple tumor-free organs of cachexic HCC mice but not in non-cachexic controls. Immunofluorescence confirmed that the infiltrating cells included CD4⁺ and CD8⁺ T cells. Morphological assessment and hematoxylin-eosin staining revealed thymic atrophy in cachexic HCC mice. Single-cell RNA sequencing of thymic stromal cells showed a reduction in medullary thymic epithelial cells (mTECs) II and III in cachexic mice. Autoimmune regulator (Aire) downregulation was accompanied by decreased expression of tissue-restricted antigens in mTECs. T cells from cachexic HCC mice induced organ-specific inflammation and T-cell infiltration in multiple organs of tumor-free mice. Following anti-mouse PD-1 antibody treatment, the incidence of inflammation in multiple organs markedly increased in cachexic HCC mice and in tumor-free mice that had received T cells from the cachexic HCC mice. Flow cytometry and immunofluorescence analyses revealed enrichment of thymic monocytic myeloid-derived suppressor cells (M-MDSCs) in cachexic HCC mice. M-MDSCs infiltrated the thymus in cachexic mice with cancer, and they induced apoptosis of mTECs from tumor-free mice in vitro via nitric oxide production. Transfer of M-MDSCs led to inflammatory cell infiltration in multiple organs and thymic involution in tumor-free mice without affecting body weight. Sixty-four patients with advanced cancer receiving anti-PD-1/L1 therapy were enrolled. Patients who developed irAEs had higher levels of circulating M-MDSCs than those who did not. Moreover, patients with cachexia (body mass index (BMI) < 20 kg/m² or >5% weight loss over the past 6 months) had elevated M-MDSC levels. Patients with both high M-MDSC levels and low BMI or weight loss >5% experienced more irAEs (hazard ratio: 2.333; 95% confidence interval: 1.231-4.423).

Conclusions: M-MDSCs in cachexic mice induced mTEC apoptosis through nitric oxide production, impairing T-cell negative selection and promoting autoimmune T-cell infiltration into tumor-free organs. Cancer cachexia-related M-MDSCs may serve as predictive biomarkers for irAEs in patients with advanced cancer.

Keywords

Cancer cachexia / Thymus involution / T-cell negative selection / Monocytic myeloid-derived suppressor cells (M-MDSCs) / Immune-related adverse events (irAEs) / Anti-PD-1/L1 therapy

Authors’ contributions

Li Wei: Writing - original draft, Visualization, Validation, Software, Writing - review & editing, Methodology, Investigation, Formal analysis, Data curation. Ya-Qin Sun: Writing - original draft, Visualization, Validation, Software, Resources, Writing - review & editing, Methodology, Investigation. Jian-Hua Ren: Validation, Methodology, Investigation, Formal analysis, Data curation, Writing - original draft, Writing - review & editing. Ze-Xuan Huang: Resources, Methodology. Yuan Zhang: Visualiza-tion, Validation, Project administration, Methodology. Xiu-Qing Pang: Visualization, Resources, Methodology. Xiao-Tong Lv: Validation, Software, Resources. Xiang-Yuan Wu: Supervision, Project administration, Funding acquisition, Conceptualization. Yan-Fang Xing: Supervision, Project administration, Funding acquisition, Conceptualization. Xing Li: Writing - original draft, Supervision, Resources, Project administration, Funding acquisi-tion, Conceptualization.

Data availability statement

All data generated and/or analyzed during this study are available from the corresponding authors upon reasonable request.

Declaration of competing interest

The authors declare that there is no conflicts of interest.

Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 82170749), the Guangdong Basic and Applied Basic Research Foundation (No. 2022A1515010465 and 2022A1515012659), Guangzhou Science and Technology Program Key Projects (No. 2023B01J1007), and the Traditional Chinese Medicine Bureau of Guangdong Province, China (No. 20241045).

Appendix A. Supplementary data

Supplementary data to this article can be found online at https://doi.org/10.1016/j.livres.2025.10.001.

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