Intratumor immune heterogeneity across simulated core biopsy sizes in non-small cell lung cancer: an exploratory study

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Background: Immune checkpoint blockade (ICB) is widely used to treat patients with non-small cell lung cancer (NSCLC). However, intratumor (immune) heterogeneity may significantly impact the therapeutic efficacy of ICBs. It remains unknown whether larger core biopsies better represent the intratumor heterogeneity. This study aimed to explore the intra- and interpatient heterogeneity of selected immune-related parameters on varying simulated biopsy core sizes. Methods: In this exploratory prospective cohort study, patients with stage I-III NSCLC who had undergone curative-intent surgery, with or without neoadjuvant chemotherapy or chemoradiation, were enrolled. Intratumor immune heterogeneity was assessed using quadruple immunofluorescence stainings (CD31, Ki67, CD4, CD8, CD68, FOXP3, PD-L1, Pan-keratin, and DAPI) on resected tumor specimens. Digital images were used to simulate biopsy cores ranging from 1- to 4-mm in diameter. Heterogeneity was quantified using the quartile coefficient of dispersion (QCD) across 250 randomly selected subregions per core size. Results: Tumor specimens from 29 patients were analyzed, including 10 patients who had received neoadjuvant therapy. Intratumor QCD values decreased significantly with increasing simulated biopsy core diameter for all markers. Nonetheless, substantial spatial heterogeneity persisted for programmed death-ligand 1 (PD-L1), with 58.8% of patients showing heterogeneous distribution, even in 4-mm simulated biopsy cores. Conclusions: Larger biopsy core sizes were associated with reduced intratumor heterogeneity for most immune markers, suggesting a better reflection of the tumor immune landscape of the whole tumor. However, PD-L1 expression remained spatially heterogeneous even in larger cores. Further validation in larger prospective cohort studies will be essential to determine the translational relevance of heterogeneity metrics and to better inform biopsy sampling strategies in routine clinical practice.

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