Prognostic significance of PD-L1 expression and CD8+ T cell infiltration in pulmonary neuroendocrine tumors

Wang, Haiyue; Li, Zhongwu; Dong, Bin; Sun, Wei; Yang, Xin; Liu, Ruping; Zhou, Lixin; Huang, Xiao; Jia, Ling; Lin, Dongmei

doi:10.1186/s13000-018-0712-1

Cited by 43 publications

(55 citation statements)

References 27 publications

(24 reference statements)

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“…Furthermore, more than half of the patients who presented with locally extended disease at diagnoses showed PD-L1 immunoreactivity, compared with only a quarter of the patients with locally confined or extended disease. Although only a limited number of NET G3 were included in our study, our data therefore confirm others who demonstrated PD-L1 expression mainly on TC of poorly rather than of well-differentiated NENs (49, 50) or who even exclusively detected PD-L1 expression in GEP-NEC (51). These results indicate, that the more aggressive the tumor, the higher the expression of PD-L1.…”

Section: Discussionsupporting

confidence: 90%

PD-L1 Expression and Immune Cell Infiltration in Gastroenteropancreatic (GEP) and Non-GEP Neuroendocrine Neoplasms With High Proliferative Activity

et al. 2019

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The potential of neuroendocrine neoplasms (NEN) to respond to checkpoint inhibitors is largely unknown and full of great expectations. Immunohistochemical (IHC) studies of programmed cell death ligand 1 (PD-L1) expression in the tumor microenvironment and its implications in predicting the response to checkpoint inhibition is a very active subject. Currently, the combined analysis of PD-L1 expression and tumor-associated immune cell (TAIC) infiltration is considered the best predictive marker of therapeutic response. Here we investigated the expression of PD-L1 on tumor cells (TC) and tumor-infiltrating immune cells (IC) by IHC in 68 NEN samples with a high proliferation rate (Ki-67 >20%) from 57 patients and in 22 samples we correlated it with TAIC density by assessing intratumoral infiltration of CD3+, CD8+, and CD68+ cells. Furthermore, the tumor microenvironment was evaluated according to the classification of Teng et al. We detected PD-L1 expression in 31.6% of NEN G3. Its expression usually was weak and more IC than TC expressed PD-L1. The proportion of tumors positive for PD-L1 was comparable in NEN from different sites of origin but varied depending on tumor differentiation and disease extension. No positive IHC staining was found in 3 well-differentiated neuroendocrine tumors (NETs) with a proliferation rate above 20% (NET G3). When analyzing TAIC, we rarely (18.2%) detected intratumoral CD8+ cells, whereas infiltration by CD3+ and CD68+ cells was more common (45.5 and 59.1%, respectively). By combining CD3+ cells and PD-L1 status, we identified the immune ignorant phenotype of tumor microenvironment as being the most common phenotype, supporting the concept of a preferably combined immunotherapeutic approach in neuroendocrine carcinoma (NEC).

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Section: Discussionsupporting

confidence: 90%

PD-L1 Expression and Immune Cell Infiltration in Gastroenteropancreatic (GEP) and Non-GEP Neuroendocrine Neoplasms With High Proliferative Activity

et al. 2019

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“…First, we noticed that PCs, especially TCs, can express PD-L1. To the best of our knowledge, only four studies on PD-L1 expression in PCs have been published earlier (16, 18, 20, 21). In all studies, PCs were pooled with LCNEC and SCLC, and patient numbers were relatively low, ranging from 22 to 57.…”

Section: Discussionmentioning

confidence: 99%

“…Several studies have investigated the expression of PD-1 and PD-L1 in SCLC but reports on PC tumors are rare and have involved only a limited number of patients (16, 17, 18, 19, 20, 21). In addition, in most studies PCs have been merged with high-grade LCNEC and SCLC which behave much more aggressively.…”

Section: Introductionmentioning

confidence: 99%

PD-1 and PD-L1 expression in pulmonary carcinoid tumors and their association to tumor spread

Vesterinen

Kuopio

Ahtiainen

et al. 2019

Endocrine Connections

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Pulmonary carcinoid (PC) tumors are rare tumors that account for approximately 1% of all lung cancers. The primary treatment option is surgery, while there is no standard treatment for metastatic disease. As the number of PCs diagnosed yearly is increasing, there is a need to establish novel therapeutic options. This study aimed to investigate programmed death protein 1 (PD-1) and programmed death ligand 1 (PD-L1) expression in PC tumors since blocking of the PD-1/PD-L1 pathway is a promising therapeutic option in various other malignancies. A total of 168 PC patients treated between 1990 and 2013 were collected from the Finnish biobanks. After re-evaluation of the tumors, 131 (78%) were classified as typical carcinoid (TC) and 37 (22%) as atypical carcinoid (AC) tumors. Primary tumor samples were immunohistochemically labeled for PD-1, PD-L1 and CD8. High PD-1 expression was detected in 16% of the tumors. PD-L1 expression was detected in 7% of TC tumors; all AC tumors were PD-L1 negative. PD-L1 expression was associated with mediastinal lymph-node metastasis at the time of diagnosis (P = 0.021) as well as overall metastatic potential of the tumor (P = 0.010). Neither PD-1 expression, PD-L1 expression nor CD8+ T cell density was associated with survival. In conclusion, PD-1 and PD-L1 were expressed in a small proportion of PC tumors and PD-L1 expression was associated with metastatic disease. Targeting of the PD-1/PD-L1 pathway with immune checkpoint inhibitors may thus offer a treatment option for a subset of PC patients.

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“…PD-L1 expression in >1% of tumour cells is present in only a minority (~20%) of SCLC specimens [5][6][7][8] . Retrospective studies of samples obtained from patients with SCLC before the introduction of ICIs have demonstrated a better prognosis in those with high counts of tumour-infiltrating lymphocytes (TILs) [17][18][19][20] . Each retrospective analysis was performed in samples from a slightly different patient population and revealed different associations.…”

Section: Immunobiology and Subtypesmentioning

confidence: 99%

“…Each retrospective analysis was performed in samples from a slightly different patient population and revealed different associations. The presence of CD8 + stromal TILs was associated with superior progression-free survival (PFS) and overall survival (OS) (both P < 0.05) in patients with pulmonary neuroendocrine tumours of any histology, 59.1% of whom had SCLC 18 . The presence of suppressive FOXP3 + regulatory T cells was found to be associated with a better prognosis in patients with limited-stage (stage I-III) SCLC (LS-SCLC) (HR 0.37, 95% CI 0.17-0.81; P = 0.013) 17 .…”

Section: Immunobiology and Subtypesmentioning

confidence: 99%

Immunotherapeutic approaches for small-cell lung cancer

2020

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Immune-checkpoint inhibitors (ICIs) are approved in the first-line and third-line settings for patients with extensive-stage or relapsed small-cell lung cancer (SCLC), respectively. In the firstline setting, the addition of the anti-programmed cell death 1 ligand 1 (PD-L1) antibody atezolizumab to chemotherapy improves overall survival (OS). In patients with relapsed disease, data from nonrandomized trials have revealed promising responses, although a significant improvement in OS over that obtained with conventional chemotherapy was not achieved in a randomized trial in this setting. Substantial research interest exists in identifying predictive biomarkers that could guide the use of ICIs in patients with SCLC. PD-L1 expression is typically low or absent in SCLC, which has precluded its use as a predictive biomarker. Tumour mutational burden might have some predictive value, although blood-based measures of tumour mutational burden did not have predictive value in patients receiving atezolizumab plus chemotherapy in the first-line setting. After three decades, ICIs have finally enabled an improvement in OS for patients with SCLC; however, a substantial amount of research remains to be done, including identifying the optimal therapeutic strategy and predictive biomarkers. In this Review, we describe the available data on clinical efficacy, the emerging evidence regarding biomarkers and ongoing clinical trials using ICIs and other immunotherapies in patients with SCLC. Small-cell lung cancer (SCLC) accounts for ~15% of all lung cancers and ~30,000 deaths in the USA annually 1. Owing to the elusive pathophysiology of the disease, the poor prognosis of patients and minimal improvement in the effectiveness of therapies over the past decades, SCLC is a US National Cancer Institute-designated recalcitrant malignancy 2. With the FDA approval of carboplatin, etoposide and the anti-programmed cell death 1 ligand 1 (PD-L1) antibody atezolizumab as a first-line therapy, and the anti-programmed cell death protein 1 (PD-1) antibodies nivolumab and pembrolizumab as monotherapies in the third-line setting, immune-checkpoint inhibitors (ICIs) have entered the treatment

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Prognostic significance of PD-L1 expression and CD8+ T cell infiltration in pulmonary neuroendocrine tumors

Cited by 43 publications

References 27 publications

PD-L1 Expression and Immune Cell Infiltration in Gastroenteropancreatic (GEP) and Non-GEP Neuroendocrine Neoplasms With High Proliferative Activity

PD-L1 Expression and Immune Cell Infiltration in Gastroenteropancreatic (GEP) and Non-GEP Neuroendocrine Neoplasms With High Proliferative Activity

PD-1 and PD-L1 expression in pulmonary carcinoid tumors and their association to tumor spread

Immunotherapeutic approaches for small-cell lung cancer

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