Myeloid and T-Cell Microenvironment Immune Features Identify Two Prognostic Sub-Groups in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms.

Published on Apr 17, 2021in Journal of Clinical Medicine3.303
· DOI :10.3390/JCM10081741
Giovanni Centonze11
Estimated H-index: 11
,
Vincenzo Lagano1
Estimated H-index: 1
+ 16 AuthorsMassimo Milione31
Estimated H-index: 31
Sources
Abstract
High-grade Gastroenteropancreatic Neuroendocrine neoplasms (H-NENs) comprehend well-differentiated tumors (NET G3) and poorly differentiated carcinomas (NEC) with proliferative activity indexes as mitotic count (MC) >20 mitoses/10 HPF and Ki-67 >20%. At present, no specific therapy for H-NENs exists and the several evidences of microenvironment involvement in their pathogenesis pave the way for tailored therapies. Forty-five consecutive cases, with available information about T-cell, immune, and non-immune markers, from surgical pathology and clinical databases of 2 Italian institutions were immunostained for Arginase, CD33, CD163 and CD66 myeloid markers. The association between features was assessed by Spearman’s correlation coefficient. A unsupervised K-means algorithm was used to identify clusters of patients according to inputs of microenvironment features and the relationship between clusters and clinicopathological features, including cancer-specific survival (CSS), was analyzed. The H-NEN population was composed of 6 (13.3%) NET G3 and 39 (86.7%) NEC. Overall, significant positive associations were found between myeloid (CD33, CD163 and Arginase) and T/immune markers (CD3, CD4, CD8, PD-1 and HLA-I). Myeloid and T-cell markers CD3 and CD8 identified two clusters of patients from unsupervised K-means analysis. Cases grouped in cluster 1 with more myeloid infiltrates, T cell, HLA and expression of inhibitory receptors and ligands in the stroma (PD-1, PD-L1) had significantly better CSS than patients in cluster 2. Multivariable analysis showed that Ki-67 (>55 vs. <55, HR 8.60, CI 95% 2.61–28.33, p < 0.0001) and cluster (1 vs. 2, HR 0.43, CI 95% 0.20–0.93, p = 0.03) were significantly associated with survival. High grade gastroenteropancreatic neuroendocrine neoplasms can be further classified into two prognostic sub-populations of tumors driven by different tumor microenvironments and immune features able to generate the framework for evaluating new therapeutic strategies.
References32
Newest
#1Alex John Liu (Mayo Clinic)H-Index: 2
#2Benjamin Edward Ueberroth (Mayo Clinic)H-Index: 1
Last. Mohamad Bassam Sonbol (Mayo Clinic)H-Index: 16
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#2Yixuan Zhang (SYSU: Sun Yat-sen University)H-Index: 3
#3Luohai Chen (SYSU: Sun Yat-sen University)H-Index: 6
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#1Abir Salwa AliH-Index: 5
#2Seppo W. LangerH-Index: 25
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#1Barbara Kiesewetter (Medical University of Vienna)H-Index: 17
#2Markus Raderer (Medical University of Vienna)H-Index: 79
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#1Massimo MilioneH-Index: 31
#2Mattia BoeriH-Index: 21
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Almost 25% of lung cancers (LCs) occur in never-smokers. LC inflammatory profile, based on plasma C-reactive protein levels (CRP), predicts mortality, independently by smoking-status. We hypothesized that: CRP could be associated with tumor immune contexture (TIC) in never-smokers and both these two parameters may improve their prognosis. Sixty-eight never-smokers LC patients with high or low CRP were selected. The programmed cell death protein 1 (PD-1) and its ligand (PD-L1), the human leukocyt...
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The 2017 World Health Organization (WHO) classification of neuroendocrine neoplasms (NEN) of the digestive tract introduced a new category of tumors named well-differentiated grade 3 neuroendocrine tumors (NET G−3). These lesions show a number of mitosis, or a Ki−67 index higher than 20% with a well-differentiated morphology, therefore separating them from neuroendocrine carcinomas (NEC) which are poorly differentiated. It has become clear that NET G−3 show differences not only in morphology but...
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#1Ting-Fang He (City of Hope National Medical Center)H-Index: 10
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The evolutionary changes in immune profiles of triple negative breast cancer (TNBC) are not well understood, although it is known that immune checkpoint inhibitors have diminished activity in heavily pre-treated TNBC patients. This study was designed to characterize immune profile changes of longitudinal tumor specimens by studying immune subsets of tumor infiltrating lymphocytes (TILs) in paired primary and metastatic TNBC in a cohort of "poor outcome" (relapsed within 5 years) patients. Immune...
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The WHO classification of digestive system tumours presented in the first volume of the WHO classification of tumours series, 5th edition, reflects important advancements in our understanding of tumours of the digestive system (Table ​(Table1).1). For the first time, certain tumour types are defined as much by their molecular phenotype as their histological characteristics; however, in most instances histopathological classification remains the gold standard for diagnosis. The WHO classification...
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#1Wu-Hu ZhangH-Index: 5
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Abstract Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a group of rare tumors that are increasing in prevalence. The complex tumor immune microenvironment (TIME) plays an important role in tumor development and the response to immunotherapy but is poorly understood. In this review, the components of the TIME are described in detail, including discussion about infiltrating immune cells, the immune checkpoint system, the cytokine and chemokine milieu, and immunomodulatory factors....
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BACKGROUND The clinical management of high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable the stratification of patients with otherwise comparable tumor features. METHODS We...
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