Association of Intratumoral Macrophage Subsets with Treatment Outcomes in Patients with Stage IV Solid Tumors

PURPOSE: To assess whether pretreatment intratumoral macrophage-associated and T-cell marker-positive areas are associated with treatment outcomes in patients with stage IV solid tumors receiving programmed cell death protein 1 (PD-1)-based immune checkpoint blockade, and whether tissue marker-positive areas correspond to peripheral blood monocyte subsets. MATERIALS AND METHODS: This retrospective, single-center study included 52 patients with metastatic or recurrent stage IV solid tumors and available pretreatment formalin-fixed, paraffin-embedded tumor tissue. Immunohistochemistry was performed for CD3, CD8, CD14, CD16, CD68, CD86, CD163, and CD206. Automated image analysis quantified chromogenic marker-positive area as a percentage of the analyzed tumor region of interest. Marker-positive areas were compared between patients with objective response, defined as complete or partial response, and those with stable or progressive disease. Associations with progression-free survival and overall survival were evaluated using median-based Kaplan-Meier analyses and Cox proportional hazards models. Correlations with peripheral blood monocyte subsets were assessed in patients with available flow-cytometry data. Exploratory sensitivity analyses were performed in the anti-PD-1 monotherapy subgroup and within major tumor types. RESULTS: Higher CD68-, CD86-, CD163-, CD206-, and CD8-positive areas were associated with longer progression-free survival and overall survival, whereas CD14-, CD16-, and CD3-positive areas were not. All six myeloid/macrophage-associated marker-positive areas and CD8-positive area were higher in patients with complete or partial response than in those with stable or progressive disease. Tissue marker-positive areas did not show consistent correlations with peripheral blood monocyte subsets. The direction of the principal associations was maintained in the anti-PD-1 monotherapy sensitivity analysis. CONCLUSIONS: Higher pretreatment CD68-, CD86-, CD163-, CD206-, and CD8-positive areas were associated with favorable outcomes during PD-1-based immune checkpoint blockade in this heterogeneous stage IV cohort. These exploratory findings do not establish a predictive biomarker or patient-selection test. Prospective validation in larger, tumor-specific cohorts is required.