HFRT study identifies ISG15+MHC-I+ neutrophils in rectal cancer
A rectal cancer study found hypofractionated radiotherapy increased ISG15+MHC-I+ neutrophils with antigen-presenting capabilities. The report linked the effect to IFN-α/NOD1 signaling and improved anti-PD-1 responses in models.
Hypofractionated radiotherapy increased ISG15+MHC-I+ neutrophil infiltration in rectal cancer and the neutrophil subset exhibited antigen-presenting capabilities that were described as crucial for successful neoadjuvant therapy. The study said HFRT promotes IFN-α release, which activates the NOD1/NF-κB pathway to drive MHC-I expression in neutrophils, and that adoptive transfer of ex vivo-generated ISG15+MHC-I+ neutrophils in mouse models enhanced intratumoral CD8+ T cell infiltration, synergizing with anti-PD-1 therapy to suppress tumor growth.
The report said previous clinical trials had demonstrated that neoadjuvant hypofractionated radiotherapy combined with immunotherapy yields promising clinical outcomes in locally advanced rectal cancer, but that the combined modality benefits only a subset of patients. It added that the current standard of care involving neoadjuvant chemoradiotherapy followed by total mesorectal excision remains suboptimal, with persistent risks of distant metastasis and locoregional recurrence compromising long-term survival outcomes.
According to the study, only about 5% of patients with locally advanced rectal cancer—those with microsatellite instability-high or mismatch repair-deficient tumors—respond well to immune checkpoint inhibitors, while the remaining 95% have a microsatellite stable or mismatch repair-proficient profile and are considered “cold” tumors. The study said overcoming immunotherapy resistance in MSS/pMMR locally advanced rectal cancer remains an urgent unmet need.
The researchers said phase II and phase III clinical trials showed that combining short-course hypofractionated radiotherapy (5Gy×5) with sequential chemotherapy and immunotherapy significantly improves pathological complete response rates. They also said earlier research revealed that hypofractionated radiotherapy induces immunogenic cell death more effectively than conventional fractionation, while the precise mechanisms by which HFRT modulates the tumor microenvironment remained incompletely understood.
Using single-cell RNA sequencing to analyze rectal cancer tissues from patients receiving HFRT, the study identified a unique immunogenic neutrophil subset characterized by co-expression of ISG15 and MHC class I molecules. The report said HFRT induces the formation of ISG15+MHC-I+ neutrophils and potentiates their antigen-presenting function through the IFN-α/NOD1 signaling axis, providing what it described as a potential strategy to convert “cold” tumors to “hot” phenotypes for enhanced immunotherapy efficacy in microsatellite stable locally advanced rectal cancer.