Desmoplasia in non-small cell lung carcinomas is associated with low programmed death-ligand 1 expression and the absence of tumor-infiltrating lymphocytes.

ABSTRACT

Programmed death-ligand 1 (PD-L1) is the most widely utilized predictive marker used to identify non-small cell lung carcinoma (NSCLC) patients most suitable for immunotherapy approaches. The relationship between PD-L1 expression, the presence of CD8+ T cells, and other clinicopathological characteristics of NSCLC patients has not been elucidated yet. In this retrospective study, we immunohistochemically determined PD-L1 expression (using clone 22C3) and CD8+ T cell count (using clone c8/144B) in surgical resection specimens from 698 advanced NSCLC patients. Results of PD-L1 expression and CD8+ T cell count were correlated to various clinicopathological characteristics, including the presence of desmoplasia in NSCLC. Regarding the immunological attributes of the tumor microenvironment, we identified major differences between desmoplastic and non-desmoplastic areas in NSCLC. Tumor areas without desmoplasia were significantly more often PD-L1 positive than tumor cell clusters encased in a dense collagenous stroma (p=0.004). Furthermore, the desmoplastic stroma contained significantly less often an immune cell infiltrate rich in CD8+ T cells (p<0.001). Also, the positivity of PD-L1 significantly correlated with advanced N-stage (p<0.001) and poor differentiation in adenocarcinomas (p=0.032) but not with other clinicopathological characteristics. In conclusion, to our knowledge, this is the first study that points to major differences in terms of immunological attributes between desmoplastic and non-desmoplastic areas in NSCLC. The desmoplastic component, therefore, may represent an immunologically distinct tumor area in which PD-L1 immunohistochemistry and CD8+ T cell count should be evaluated separately.