CD68+ tumor-associated macrophages exhibit prognostic value in surgically resected small cell lung cancer: a retrospective cohort study of 614 patients.

Abstract

Background: Tumor-associated macrophages (TAMs) are key components of the tumor microenvironment (TME) in small cell lung cancer (SCLC), yet the clinicopathological and prognostic relevance of CD68⁺ TAM infiltration in surgically resected SCLC remains insufficiently defined. We aimed to delineate the clinical significance of CD68⁺ cell density in surgically resected SCLC and develop an immune-integrated prognostic nomogram.

Methods: We retrospectively enrolled 614 patients with surgically resected SCLC from January 2000 to December 2022. CD68⁺ cell density and ASCL1/NeuroD1/POU2F3/YAP1 expression were assessed by immunohistochemistry. Cox regression identified independent prognostic factors, and nomograms were built and validated. Bulk transcriptomic analyses and immune deconvolution were performed to interpret CD68-associated biological programs. IHC staining for CD163, CD3, and CD8 was performed on a subset of 83 cases to validate computational findings at the tissue level.

Results: In surgically resected SCLC samples, the median CD68⁺ cell density was 922.4/mm². CD68-high tumors showed higher proportions of NeuroD1 high expression, POU2F3 positivity, and YAP1 positivity (all p < 0.05). Clinically, CD68-high status correlated with earlier T/N stage and fewer adverse invasion features (p < 0.05). CD68-high infiltration was independently associated with improved overall survival (p < 0.01) and disease-free survival (p < 0.05); stratified Kaplan-Meier analyses confirmed that this prognostic benefit persisted within clinically homogeneous T-stage, N-stage, and TNM-stage subgroups (10 of 12 analyses, p < 0.05). Nomograms incorporating CD68⁺ density and clinicopathological factors demonstrated favorable discrimination and calibration. Transcriptomic profiling and GSEA indicated that CD68-high SCLC were enriched for myeloid/chemokine signaling, antigen presentation, and T-cell-related pathways. Immune deconvolution supported higher monocytic lineage signals and elevated MHC components in CD68-high tumors, with correlation patterns consistent with M1-like macrophage signatures. IHC validation of CD163, CD3, and CD8 on 83 cases confirmed globally enhanced immune infiltration in CD68-high tumors, although the unchanged CD68/CD163 ratio indicated a proportional increase across macrophage subsets rather than a selective M1 shift.

Conclusions: High CD68+ macrophage infiltration is an independent favorable prognostic factor in surgically resected SCLC. Transcriptomic and deconvolution analyses suggest that the CD68-defined immune heterogeneity is consistent with M1-like macrophage enrichment, although this inference is based on computational deconvolution. Preliminary IHC validation with CD163, CD3, and CD8 on a subset of 83 cases confirmed globally enhanced immune infiltration in CD68-high tumors. A CD68-integrated prognostic nomogram was constructed for surgically resected SCLC patients.