Pre-existing tumor host immunity characterization in resected non-small cell lung cancer.

Introduction: Neoadjuvant and adjuvant immune checkpoint blockade (ICB) have recently become standard of care in resectable non-small cell lung cancer (NSCLC). Yet, biomarkers that inform patients who benefit from this approach remain largely unknown. Here, we interrogated the tumor immune microenvironment (TIME) in early-stage NSCLC patients that underwent up-front surgery.
Methods: A total of 185 treatment-naïve patients with early-stage NSCLC, that underwent up-front surgical treatment between 2006 and 2018 at Hospital del Mar were included. 124 lung adenocarcinomas (LUADs), and 61 squamous cell carcinoma (LUSCs) were included in a tissue microarray. Immunohistochemistry for CD3, CD4, CD8, CD68, CD80, CD103, FOXP3, PD-1, PD-L1, PD-L2 and HLA class II were evaluated by digital image analysis (QuPath software). TIME was categorized into four groups using PD-L1 expression in tumor cells (<1 % or ≥1 %) and tumor resident memory (CD103 ⁺ ) immune cells (using the median as cut-off). We explored the association between different TIME dimensions and patient's clinicopathological features and outcomes.
Results: We found increased levels of T cell markers (CD3 ⁺ , CD4 ⁺ , CD8 ⁺ cells), functional immune markers (FOXP3 ⁺ cells) as well as, higher HLA-II tumor membrane expression in LUADs compared to LUSCs (p < 0.05 for all). In contrast, LUSCs displayed higher percentage of intratumor macrophages (CD68 ⁺ cells) as well as, higher PD-L1 and PD-L2 tumor membrane expression (p < 0.05 for all). Unsupervised analysis revealed three different tumor subsets characterized by membrane tumor expression of PD-L1, PD-L2 and HLA-class II. Enrichment of T cells (CD3 ⁺ , CD8 ⁺ cells), regulatory T cells (FOXP3 ⁺ cells) and macrophages (CD68 ⁺ cells) was observed in the CD103 ⁺ /PD-L1 ⁺ group (p < 0.05 for all). Multivariate analysis showed that infiltration by CD103 ⁺ immune cells was associated with improved OS (p = 0.009).
Conclusions: TIME analysis in resected NSCLC highlighted differences by histology, PD-L1 expression and molecular subgroups. Biomarker studies using IHC might aid to individually tailor adjuvant treatment in early-stage NSCLC.
Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:P. Rocha reports travel support from AstraZeneca. A. Taus reports personal fees and non-financial support from Takeda, Sanofi, Roche, BMS, MSD, GSK, Astrazeneca and Pfizer, outside the submitted work. R. Chalela reports travel and personal fees from Chiesi, GSK and AstraZeneca, outside the submitted work. B. Bellosillo reports grants, personal fees and non-financial support from Roche, grants, personal fees and non-financial support from ThermoFisher, grants, personal fees and non-financial support from Astra-Zeneca, personal fees and non-financial support from Merck-Serono, personal fees and non-financial support from Novartis, personal fees and non-financial support from Qiagen, personal fees and non-financial support from Pfizer, personal fees and non-financial support from BMS. L. Comerma reports personal fees and non-financial support from Roche, personal fees and non-financial support from MSD and personal fees from Diaceutics, outside the submitted work. E. Arriola reports grants, personal fees and non-financial support from Roche, personal fees, and non-financial support from BMS, personal fees and non-financial support from MSD, personal fees from Astra Zeneca, grants and personal fees from Pfizer, personal fees and non-financial support from Boehringer Ingelheim, personal fees and non-financial support from Lilly, personal fees from Takeda, outside the submitted work. Remain authors have no competing interests to declare.
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