Cross-Cancer Analysis Reveals a Distinct Pattern of Immune Modulation During Curative Radiation Therapy.

Abstract

Radiation therapy (RT) is a cornerstone of curative cancer treatment, yet its immune effects are not fully understood. This study examined systemic immune profile changes in patients undergoing RT for solid tumors. Patients with localized head and neck cancer, non-small cell lung cancer, rectal cancer, or extremity soft tissue sarcoma treated with curative RT (>45 Gy, 1.8-3 Gy/fraction) were enrolled. Baseline and post-RT (after 45 Gy) blood samples were analyzed using multiplex Luminex cytokine assays and high-dimensional mass cytometry (cytometry by time-of-flight). Immune alterations were correlated with patient outcomes. Thirty-seven patients treated with curative RT for head and neck cancer (n = 8), non-small cell lung cancer (n = 8), rectal cancer (n = 7) or soft tissue sarcoma (n = 14) were enrolled. Approximately 50% of patients received concurrent chemotherapy. At a median follow-up of 21 months, there were 3 local and 12 distant recurrences. Cytokine analysis showed increased C-X-C motif chemokine ligand 12 (P = .044) and monocyte chemoattractant protein-1 (P < .001), both important in monocyte trafficking and mobilization. Consistent with the cytokine changes, cytometry by time-of-flight demonstrated increased monocytes (P < .001) and reduced natural killer and B cells (P < .001). Circulating CD4 effector T cells decreased in patients who developed distant metastases (P = .049) but remained unchanged in recurrence-free patients. These effects were independent of tumor type and chemotherapy, indicating conserved immune changes following RT. We identified a distinct pattern of immune change across all tumor types analyzed in response to RT, with increases in protumoral myeloid cell populations, reductions in B cells and natural killer cells, and a significant decrease in CD4 effector T cells among patients who developed distant metastases.