Intratumoral Immune Heterogeneity Drives Divergent Outcomes to PD-(L)1 Blockade in Lung Cancer
- Journal
- Clinical cancer research : an official journal of the American Association for Cancer Research (Q1)
- Published
- 15 July 2026
- Study design
- Unclassified
- Evidence level
- Level 5, Expert Opinion (CEBM 5)
- Authors
- Laura Cipriani, Davide Mascolo, Stefano Scalera, Giulia Bon, Giulia Schiavoni, Antonella Palmese, et al.
- PMID
- 42456046
- DOI
- 10.1158/1078-0432.CCR-26-1466
Why clinicians should know about it
- Picked for Pathology and Forensic Medicine (paper of the day, 16 July 2026).
Abstract
PURPOSE: Clinical outcomes with immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) range from durable disease control to rapid progression. Current biomarkers have limited ability to predict these divergent outcomes. EXPERIMENTAL DESIGN: Spatially-resolved immune subtyping in the TRACERx421 multiregion cohort was used to assess intratumoral immune heterogeneity (ITIH), defined as coexisting immune-enriched and immune-depleted regions. A computational model was used to infer ITIH from single samples, classifying tumors as homogenously immune-enriched (Hom-IE), heterogeneously immune-enriched (Het-IE), heterogeneously immune-depleted (Het-D), and homogenously immune-depleted (Hom-D). ITIH was validated by digital pathology and evaluated in three independent cohorts (n=1,085) of advanced NSCLC patients treated with ICIs. RESULTS: In TRACERx421, ITIH was associated with differences in immune programs among tumors otherwise classified within the same immune subtype. Single-sample ITIH inference recapitulated these patterns, as supported by gradients of tumor-infiltrating lymphocytes detected via digital pathology. Across cohorts, Hom-IE tumors demonstrated longer OS compared to other groups (34.6 vs. 12.1-16.6 months in cohort A; 21.9 vs. 8.4-13.3 months in cohort B; 22.6 vs. 11.3-13.4 months in cohort C). Hom-IE tumors were associated with longer OS regardless of PD-L1 status. Consistently, among PD-L1 low/negative tumors, Hom-IE tumors showed significantly longer OS compared to the non-Hom-IE counterpart. Conversely, the detrimental effects of KEAP1STK11 mutations persisted in the Hom-IE background. CONCLUSIONS: These findings demonstrate that ITIH can be assessed from individual tumor samples, identifies a microenvironment state associated with long-term benefit from immunotherapy, and provides an additional layer of resolution to established and emerging biomarkers.
Abstract as published, via PubMed.
For healthcare professionals. The summary is generated by AI from the published abstract, and the evidence level is assigned automatically from the study design on the Oxford CEBM hierarchy. Neither is medical advice. Read the full paper before changing practice.