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. 2021 Apr 17;10(8):1741.
doi: 10.3390/jcm10081741.

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

Giovanni Centonze  1   2 , Vincenzo Lagano  1 , Giovanna Sabella  1 , Alessandro Mangogna  3 , Giovanna Garzone  1 , Martina Filugelli  1 , Beatrice Belmonte  4 , Laura Cattaneo  1 , Valentina Crisafulli  1 , Alessio Pellegrinelli  5 , Michele Simbolo  6 , Aldo Scarpa  6   7 , Paola Spaggiari  8 , Tatiana Brambilla  8 , Sara Pusceddu  9 , Natalie Prinzi  9 , Andrea Anichini  2 , Claudio Tripodo  4 , Massimo Milione  1
Affiliations

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

Giovanni Centonze et al. J Clin Med. .

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.

Keywords: gastroenteropancreatic neuroendocrine neoplasms; myeloid markers; tumor microenvironment.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Binary associations of all investigated markers by Spearman correlation analysis. Only significant r values (either positive or negative) are shown. Expression of each marker was evaluated in the tumor (superscript T) or in the stroma (superscript S). On the bottom left: a representative scatter plot of CD8S and CD33S marker expression.
Figure 2
Figure 2
The biplot of unsupervised K-means analysis for myeloid ArginaseS, CD33S and CD66S and T-cell CD3S and CD8S.
Figure 3
Figure 3
Barplots of immunohistochemistry Score Expression of Myeloid, T-cells, Immune checkpoint and HLA markers. * indicates the level of significance.
Figure 4
Figure 4
Cancer-specific survival of patients with high-grade neuroendocrine neoplasms according cluster (A) and Ki-67 55% cut off (B).
See this image and copyright information in PMC

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