100651 - VISTA overexpression and impaired IgE signaling in lung cancer patients with allergic phenotype: implications for anti-PD-L1 response

Immune checkpoint inhibitors targeting PD-L1 show variable efficacy in non-small cell lung cancer (NSCLC). The atopic phenotype may modulate the tumor immune microenvironment through Th2-skewed responses. We hypothesized that lung cancer patients with confirmed atopic sensitization exhibit a distinct immunological signature, including altered expression of immune checkpoint and IgE-pathway genes, that may influence the outcomes of anti-PD-L1 treatment.

Thirty-two lung cancer patients receiving first-line anti-PD-L1 therapy and sixteen healthy controls were enrolled. This study represents an expansion of a previously reported pilot cohort, with systematic stratification by atopic sensitization status. Atopic sensitization was assessed by skin prick testing (SPT). Gene expression (qPCR) of VISTA, FCER2, FCGR1, MS4A2, and HRH1 was quantified in peripheral blood. Serum IgE and eosinophil counts were measured. Clinical variables included the Charlson Comorbidity Index, Tumor Proportion Score (TPS), PD-L1, pack-year index, treatment cycles, and best response per RECIST (Response Evaluation Criteria in Solid Tumors). Patients were stratified into SPT-positive (n=10) and SPT-negative (n=22) groups. Kruskal-Wallis and Mann-Whitney U tests were applied.

Compared to controls, lung cancer patients showed significantly higher VISTA expression (p=0.039), lower FCER2 (p=0.001), elevated IgE (p=0.049), and eosinophilia (p=0.011). SPT-positive patients exhibited the most pronounced VISTA overexpression (3.81 vs. 2.50 in controls; p=0.002) and the most significant FCER2 downregulation (p=0.007), alongside markedly elevated IgE levels (668 vs. 269 IU/mL in SPT-negative; p=0.001). TPS PD-L1 and Charlson index were comparable between SPT-positive and SPT-negative groups, ruling out confounding by tumor PD-L1 expression or comorbidity. SPT-positive patients had a lower objective response rate (50% vs 84%) and a shorter median progression-free survival (8.5 vs 14.8 months) than SPT-negative patients. However, these differences did not reach statistical significance.

Lung cancer patients with confirmed atopic sensitization display a paradoxical immune profile, i.e., elevated IgE, downregulated FCER2, and overexpressed VISTA, suggesting a functionally truncated Th2 response combined with enhanced non-PD-L1 checkpoint suppression. This profile correlates with a trend toward worse anti-PD-L1 outcomes, independent of PD-L1 tumor expression. VISTA may represent a relevant resistance mechanism in lung cancer patients with allergic sensitization and a potential target for combined checkpoint blockade. These findings require validation in larger cohorts.