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The combination of chemoradiotherapy (CRT) and immune checkpoint inhibition (ICI) in unresectable stage III NSCLC yields markedly divergent outcomes depending on treatment sequencing: consolidation ICI following CRT confers significant survival benefits,¹ whereas concurrent administration fails to improve survival.² This paradox implicates radiation-induced remodeling of the tumor-immune microenvironment as a key, yet poorly understood, determinant of ICI response.
We applied Opal multiplex immunofluorescence (AKOYA Biosciences) to resected NSCLC following neoadjuvant chemotherapy (CHT, n=16), CRT (n=22), or primary resection (n=10), with matched pre-treatment biopsies in a subset. A six-plex panel (CD8, CD4, FOXP3, CD20, CD68, PanCK) was quantified in QuPath to profile the immune composition across tissue compartments and classify the tumor ecosystem by KNN into inflamed, excluded, and cold phenotypes.
Tumors resected after CRT showed selective depletion of CD20+ B cells at the invasive margin compared to CHT and primary resection (p=0.01). FOXP3+ regulatory T cell density also differed significantly across treatment groups (p=0.02), with highest density observed after CHT, while CD8+ effector infiltration was preserved following CRT and CHT. These findings suggest cytotoxic treatment preferentially remodels humoral and immunoregulatory compartments at the tumor-stroma interface, revealing spatial immune barriers relevant to subsequent immunotherapy response.
Bibliography
¹Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non–small-cell lung cancer. J Clin Oncol. 2022;40(12):1301-1311. doi:10.1200/JCO.21.01308
² Bradley JD, Sugawara S, Lee KH, et al. Simultaneous durvalumab and platinum-based chemoradiotherapy in unresectable stage III non–small cell lung cancer: the phase III PACIFIC-2 study. J Clin Oncol. 2025;43(33):3610-3621. doi:10.1200/JCO-25-00036
