Stereotactic ablative radiotherapy-driven immunosuppression is associated with poorer progression-free survival in cancer patients.

BACKGROUND: The landscape of cancer treatment has evolved rapidly within the last 50 years, and whilst radiotherapy, chemotherapy, and surgery remain the mainstay treatment options, there has been a shift towards using immunotherapy alone or in combination with other treatment modalities. There is an emerging paradigm that radiotherapy is immunogenic, driving stimulation of antigen-specific T cells capable of recognising tumour cells at distal sites to the treatment location. METHODS: Whole blood samples were collected from patients with primary and oligometastatic cancer before, during, and after treatment with stereotactic ablative radiotherapy (SABR). Using clinical full blood counts, multiparameter flow cytometry, Luminex, and ELISpot assays, this study explored the impact of SABR on systemic immune cell composition, inflammatory markers, and antigen-specific T cell responses. RESULTS: We identified striking systemic changes collectively indicating profound SABR-driven immunosuppression. Such changes were characterised by pronounced and sustained lymphopenia which included loss of CD4+ and CD8+ T cells, B cells, and natural killer (NK) cells accompanied by an overall decline in effector T cell responses to common recall and cancer antigens. This loss of lymphocytes drove a rise in the neutrophil-to-lymphocyte ratio (NLR), which was associated with poorer progression-free survival (PFS) if increased from baseline. A higher dosage of radiation and treatment to a larger area were both associated with more pronounced lymphocyte loss, a concomitant NLR increase, and poorer PFS, particularly in individuals with liver lesions. CONCLUSIONS: These findings support a role for lymphocytes in preventing disease progression after SABR and suggest that a change to clinical practice to spare lymphocytes from the toxic effects of irradiation may have beneficial effects for patients.