Evaluation of immune microenvironment in non-small cell lung carcinoma after neoadjuvant immunotherapy. A case report

Immune checkpoint inhibitors are increasingly used in neoadjuvant non-small cell lung carcinoma (NSCLC). Data regarding histologic features of the tumor microenvironment in this group of patients are limited. This study aimed to analyze the histologic features and the immune cell infiltrates within the tumor microenvironment of NSCLC after neoadjuvant immunotherapy. We evaluated surgical specimens of four NSCLC patients with different pathologic responses, who underwent chemo-immune neoadjuvant therapy. The following markers were analyzed by IHC: CD3, CD4, CD8 (T cells), CD21, CD20, CD138 (DCs, B and plasma cells), CD56 (NK), CD68 (Macrophages), Perforin, Granzyme, CD137 (active-T-cells), FOXP3 (regulatory-T-cells), IgM, and PD-L1. Multiple areas of equal size were counted. These counts were correlated with tumor regression grade (TRG) and response to therapy. The prevalence of tertiary lymphoid structures, low cytotoxic (CD8+) T lymphocyte count, high expression of CD137 and CD137/FOXP3 ratio, and low expression of PD-L1 from immune cells within the tumor microenvironment were associated with high TRG and therapy responsiveness. The expression of other markers was not significantly different according to outcome. Our results highlight the importance of CD137 expression and CD137/FOXP3 ratio on immune cells as activation markers. Further studies will be needed to investigate its value as a possible predictive marker of responsiveness to immunotherapy. The unexpected findings of this study (namely, low count of cytotoxic cells in cases with high TRG) may be explained by considering the period between immunotherapy and histological evaluation.