Stromal B7-H3 Expression Characterizes an Immune-Hot Microenvironment and Predicts Response to PD-1 Blockade in Gastric Cancer.

PURPOSE: We evaluated whether B7-H3, particularly stromal B7-H3, is associated with clinical benefit from programmed cell death protein 1 (PD-1) blockade in gastric cancer (GC) and characterized the immune context underlying this association.

MATERIALS AND

METHODS

B7-H3 expression was evaluated by conventional and multiplex immunohistochemistry (m-IHC) in a discovery cohort of 124 patients with GC receiving PD-1 inhibitor-based therapy and in an independent single-center validation cohort of 40 patients. Associations with treatment response and progression-free survival (PFS) were assessed using categorical tests, Kaplan-Meier analysis, and Cox regression. An exploratory cohort of 40 patients who had not received PD-1 blockade was analyzed to assess the general prognostic association of B7-H3. Host B7-H3 was further examined in a subcutaneous mouse forestomach carcinoma (MFC) tumor model using Cd276-deficient mice, with immune profiling and RNA sequencing after PD-1 blockade.

RESULTS

In the discovery cohort, B7-H3 expression was significantly higher in responders (P < 0.0001), and high B7-H3 expression was associated with longer PFS (P = 0.0030). In the validation cohort, the objective response rate was 64.0% in the B7-H3-high group versus 26.7% in the B7-H3-low group (P = 0.0484), and B7-H3-high patients had longer PFS (P = 0.0315). Cell-type-specific m-IHC showed stronger associations for B7-H3+/α-SMA+, B7-H3+/CD31+, and B7-H3+/CD68+ stromal compartments than for B7-H3+/PanCK+ tumor cells. B7-H3 also correlated positively with PD-L1 and triplet cell cluster (TCC) infiltration. In the exploratory non-PD-1 cohort, high B7-H3 expression showed a nonsignificant trend toward higher mortality (HR = 1.548, 95% CI 0.932-2.571, P = 0.091). Following PD-1 blockade, wild-type tumors showed greater tumor control and higher CD8+, CD4+, and natural killer (NK)-cell infiltration than Cd276-deficient tumors.

CONCLUSIONS

Stromal B7-H3 is a candidate biomarker associated with favorable outcomes after PD-1 blockade and may mark an immune-engaged microenvironment with pre-existing immune-cell infiltration. These findings support prospective, multicenter evaluation of B7-H3 for patient stratification rather than establishing it as a clinically validated companion diagnostic.