Cancer Cachexia-related Monocytic MDSCs Impair T-cell Negative Selection and Predict Immune-related Adverse Events

Abstract

Background Cancer cachexia is prevalent in multiple cancers and is associated with chemotherapy toxicity. However, data on the relationship between immune-related adverse events (irAEs) and cachexia are limited. Methods A murine model of orthotopic hepatocellular carcinoma (HCC) with cachexia was constructed to determine the effect of T-cell infiltration in multiple tumor-free organs on irAEs occurrence. Single-cell sequencing of thymic stromal cells was conducted. Patients with advanced cancers receiving anti-PD-1/L1 antibody treatment were followed up to investigate the relationship between cachexia and irAEs. Results Inflammatory cells infiltrated multiple tumor-free organs in cachexic HCC but not in non-cachexic mice. Immunofluorescence revealed that these infiltrating cells included CD4⁺ and CD8⁺ T-cells. Morphological assessment and hematoxylin-eosin staining confirmed thymus atrophy in cachexic HCC mice. Single-cell sequencing of thymic stromal cells showed fewer medullary thymic epithelial cells (mTECs) II and III in the thymus of cachexic mice than in those of non-cachexic mice. Aire downregulation was accompanied by decreased expression of tissue-restricted antigens in mTECs. T cells from cachexic HCC mice induced inflammation and T cell infiltration in multiple organs of tumor-free mice in an organ-specific manner. After administration of anti-mouse PD-1 antibody, the incidence of inflammation in multiple organs was much higher in cachexic HCC mice as well as tumor free mice transferred with T cells from cachexic HCC mice. Thymic monocytic myeloid-derived suppressor cells (M-MDSCs) enriched in cachexic HCC mice, evidenced by flow cytometer and immunofluorescence analyses. M-MDSCs infiltrated the thymus in cachexic mice with cancer. Cachexia-related M-MDSCs induced mTEC from tumor-free mice apoptosis through nitric oxide production in vitro. M-MDSCs transfer induced infiltration of inflammatory cells in multiple organs and thymus involution of tumor free mice without decreasing their weights. Sixty-four patients with advanced cancer receiving anti-PD-1/L1 antibody treatment were included in this study. Patients with irAEs displayed higher levels of circulating M-MDSCs than those without irAEs. Moreover, patients with cachexia (BMI < 20 kg/m² or weight loss ≥ 5% over the past 6 months) had higher M-MDSC levels. Patients with high M-MDSC levels and low BMI or weight loss ≥ 5% experienced more irAEs (HR 2.333, 95% CI 1.231–4.423). Conclusions M-MDSCs induced mTEC apoptosis through nitric oxide production in cachexic mice with cancer, impairing T-cell negative selection and leading to autoimmune T-cell infiltration in tumor-free organs. Cancer cachexia-related M-MDSCs are potential predictive biomarkers of irAEs in patients with advanced cancer.