Immune checkpoint inhibitors (ICIs), including antibodies against the programmed cell death protein 1/ligand 1 (PD-1/L1) effectively at boost the immune system; however, they may cause immune-related adverse events (irAEs). The predictive biomarkers and risk factors for irAEs have not been determined. Further, while activated T-cell infiltration of tissues is a hallmark of irAEs, it remains unclear if this is a prerequisite for irAEs development or merely a consequence.
To that end, a team of researchers from The Third Affiliated Hospital of Sun Yat-sen University in Guangzhou, China, investigated key immune cell subsets implicated in irAE development.
"We focused on monocytic myeloid-derived suppressor cells (M-MDSCs) associated with cancer cachexia—an often-overlooked complication of advanced cancer—and found a critical mechanism," shares co-corresponding author Xing Li. "These cachexia-related M-MDSCs induce apoptosis of medullary thymic epithelial cells (mTECs) through the production of nitric oxide (NO)."
The mTEC apoptosis, in turn, impairs thymic T-cell negative selection—a process crucial for eliminating autoimmune T cells. The autoimmune T cells that evade this selection then infiltrate non-tumor organs, acting as a core prerequisite for irAE occurrence.
The findings, published in the KeAi journal Liver Research, establish a link between cancer cachexia and irAEs—two major complications of advanced cancer that were previously regarded as independent.
"These insights into the cross-talk between cachexia-related immune dysregulation and autoimmune responses open up new avenues for developing combined interventions targeting both cachexia and irAEs, which could improve the overall prognosis of cancer patients," says Li. "The study highlights the necessity of exploring targeted strategies that capitalize on this mechanism, which could potentially transform our ability to predict and manage irAEs more effectively."
