Inflammation and PD-L1 expression in pulmonary neuroendocrine tumors

Abstract

In the light of novel cancer immune therapies, the status of antitumor inflammatory response and its regulation has gained much attention in patients with lung cancer. Ample datasets exist for non-small-cell lung cancer, but those for pulmonary neuroendocrine tumors are scarce and controversial. Here, tumor-associated inflammation, CD8+ cell infiltration and PD-L1 status were evaluated in a cohort of 57 resected carcinoids and 185 resected neuroendocrine carcinomas of the lung (58 large cell carcinomas and 127 small cell carcinomas). Data were correlated with clinicopathological factors and survival. Moderate or high tumor-associated inflammation was detected in 4 carcinoids (7%) and in 37 neuroendocrine carcinomas (20%). PD-L1 immunoreactivity was seen in immune cells of 73 (39%) neuroendocrine carcinomas, while tumor cells were labeled in 21 (11%) cases. Inflammatory cells and tumor cells in carcinoids lacked any PD-L1 expression. In neuroendocrine carcinomas, PD-L1 positivity in immune cells, but not in tumor cells, was associated with intratumoral CD8+ cell infiltration ( < 0.001), as well as with the severity of tumor-associated inflammation ( < 0.001). In neuroendocrine carcinomas, tumor-associated inflammation and PD-L1 positivity in immune cells correlated with prolonged survival and the latter factor was also an independent prognosticator ( < 0.01, hazard ratio 0.4 for overall survival, < 0.001 hazard ratio 0.4 for disease-free survival). Taken together, in neuroendocrine tumors, antitumor inflammatory response and PD-L1 expression are largely restricted to neuroendocrine carcinomas, and in this tumor entity, PD-L1 expression in inflammatory cells is positively correlated to patient survival.

Clinicopathological Profiling of Lung Carcinoids with a Ki67 Index &#x3e; 20%

“…In 181 (74%) cases, the original pathology diagnosis provided from the contributing institutions was available. The same cohort was either partly or fully included in 2 previously published studies [20, 21], one that dealt with small-cell carcinoma of the esophagus in comparison to SCLC, and the other with PD-L1 expression and survival in lung NENs. Clinical and follow-up data were available in 227 (93%) and 226 patients (93%), respectively.…”

Immune Checkpoint Inhibitors in the Treatment of Patients with Neuroendocrine Neoplasia

“…In NENs, PD-L1 expression was detected in metastatic gastroenteropancreatic (GEP)-NENs, in particular in high-grade tumors [18,19], poorly differentiated NENs [20,21], and GEP-NECs [22]. In lung NECs, PD-L1 positivity was mainly detected in tumor-infiltrating immune cells [7], less in tumor cells themselves. Furthermore, PD-1 and its ligands appear to be also expressed in well-differentiated intestinal and pancreatic NETs [23,24].…”

“…Furthermore, PD-1 and its ligands appear to be also expressed in well-differentiated intestinal and pancreatic NETs [23,24]. Conflicting results have been reported on PD-1 and PD-L1 as prognostic factors, since their expression was associated with worse overall survival in patients with pulmonary and metastatic GEP-NENs [18,25], whereas in lung NECs, both tumor-associated inflammation and PD-L1 positivity correlated with prolonged survival [7]. …”

“…T-cell tumor infiltration has been associated with patient survival in intermediate-grade primary NETs and liver metastases [4], and infiltration with regulatory T cells, with shorter survival in carcinoids [5]. Recently, T-cell infiltration and moderate to high tumor-associated inflammation was observed in 7% of lung carcinoids and 20% of lung NECs [7]. However, although NETs possess immunogenic epitopes that can be recognized by CD8+ T cells [8], solid evidence is still lacking that immune cells can effectively recognize NET cells and develop immune memory.…”

Avaliação dos genes envolvidos na transição epitelial-mesenquimal e sua relação com a progressão e a invasão tumoral em câncer de pulmão

“…Ohigashi et al and Thompson et al reported that high tumor-cell expression of PD-L1 was associated with poor survival in patients with renal-cell carcinoma, gastric and esophageal malignancies. In contrast, the predictive function for PD-L1 hyper expression in lung cancer is controversial and negative or positive prognosis associations have been reported continually [17,18]. Nevertheless, clinical trial results have led to the approval of PD-1/PD-L1 checkpoint inhibitors for the treatment of advanced NSCLC [19,20,21,22].…”