ArticleFrontiers in immunology2026
Context-dependent value of HLA class I diversity in advanced non-small cell lung cancer treated with immune checkpoint blockade.
Article in Frontiers in immunology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Background: Immune checkpoint inhibitors (ICI), alone or in combination with chemotherapy, are the standard first-line treatment for advanced non-small cell lung cancer (NSCLC) without actionable oncogenic drivers. Programmed death-ligand 1 (PD-L1) expression and tumor mutational burden (TMB) are routinely used biomarkers, yet both show limited predictive accuracy at the individual level, particularly in the context of chemo-immunotherapy. HLA class I diversity has been proposed as a biomarker of response to ICI monotherapy, although its role in first-line chemo-immunotherapy remains unclear. Methods: We performed a retrospective validation and exploratory study including patients with stage IV NSCLC treated with ICI monotherapy or platinum-based chemo-immunotherapy in the first-line setting. Tumors were profiled using a single clinically-validated targeted sequencing assay (TruSight Oncology 500), allowing simultaneous assessment of TMB and HLA class I diversity. Furthermore, tumors had a complete clinical annotation, including the level of PD-L1 expression. Associations with objective response rate (ORR) and progression-free survival (PFS) were evaluated. Results: PD-L1 expression and TMB showed limited discriminative performance for ORR, particularly in chemo-immunotherapy-treated patients. Composite HLA class I diversity did not predict ORR or PFS. A triple-negative biomarker profile identified a subgroup with reduced likelihood of response, although statistical significance was not reached. Exploratory analyses suggested that locus-specific HLA-B diversity, when combined with TMB, was associated with numerically longer PFS, whereas HLA-A, HLA-C, and composite HLA metrics showed no consistent association. Conclusions: In advanced NSCLC treated predominantly with first line chemo-immunotherapy, composite HLA class I diversity does not improve outcome prediction beyond established biomarkers. Locus-specific HLA metrics, particularly HLA-B, may warrant further investigation.
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