Aggressive Behavior in Silent Subtype III Pituitary Adenomas May Depend on Suppression of Local Immune Response: A Whole Transcriptome Analysis

Timothy E. Richardson, Zhong Jian Shen, Mohammed Kanchwala, Chao Xing, Alexander Filatenkov, Ping Shang, Samuel Barnett, Zahidur Abedin, James S. Malter, Jack M. Raisanen, Dennis K. Burns, Charles L. White, Kimmo J. Hatanpaa

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3 Citations (Scopus)

Abstract

Silent subtype III pituitary adenomas (SS-3) are clinically nonfunctional adenomas that are more aggressive in terms of invasion and risk of recurrence than their conventional null cell counterparts. We previously showed that these tumors can be distinguished by immunohistochemistry based on the identification of a markedly enlarged and fragmented Golgi apparatus. To understand the molecular correlates of differential aggressiveness, we performed whole transcriptome sequencing (RNAseq) on 4 SS-3 and 4 conventional null cell adenomas. The genes that were highly upregulated in all the SS-3 adenomas included 2 secreted proteins involved in the suppression of T-lymphocyte activity, i.e., ARG2 (multiple testing adjusted padj = 1.5 × 10-3) and SEMA3A (padj = 3.3 × 10-3). Highly downregulated genes in all the SS-3 adenomas included HLA-B (padj = 3.3 × 10-6), suggesting reduced antigen presentation by the adenoma to cytotoxic T-cells. Quantitative RT-PCR of these genes performed on the adenoma samples supported the RNAseq results. We also found a relative decrease in the overall concentration of T-lymphocytes in the SS-3 tumors. These results suggest that SS-3 adenomas actively suppress the immune system and raise the possibility that they may be treatable with immune checkpoint inhibitors or nonspecific cancer immunotherapies.

Original languageEnglish (US)
Pages (from-to)874-882
Number of pages9
JournalJournal of Neuropathology and Experimental Neurology
Volume76
Issue number10
DOIs
StatePublished - Oct 1 2017

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Pituitary Neoplasms
Gene Expression Profiling
Adenoma
Null Lymphocytes
T-Lymphocytes
Genes
Neoplasms
HLA-B Antigens
Antigen Presentation
Golgi Apparatus
Transcriptome
Immunotherapy
Immune System
Down-Regulation
Immunohistochemistry
Recurrence
Polymerase Chain Reaction
Proteins

Keywords

  • ARG2
  • HLA-B
  • Null cell adenoma
  • Pituitary adenoma
  • SEMA3A
  • Silent subtype III
  • Transcriptome sequencing

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Neurology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Cite this

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title = "Aggressive Behavior in Silent Subtype III Pituitary Adenomas May Depend on Suppression of Local Immune Response: A Whole Transcriptome Analysis",
abstract = "Silent subtype III pituitary adenomas (SS-3) are clinically nonfunctional adenomas that are more aggressive in terms of invasion and risk of recurrence than their conventional null cell counterparts. We previously showed that these tumors can be distinguished by immunohistochemistry based on the identification of a markedly enlarged and fragmented Golgi apparatus. To understand the molecular correlates of differential aggressiveness, we performed whole transcriptome sequencing (RNAseq) on 4 SS-3 and 4 conventional null cell adenomas. The genes that were highly upregulated in all the SS-3 adenomas included 2 secreted proteins involved in the suppression of T-lymphocyte activity, i.e., ARG2 (multiple testing adjusted padj = 1.5 × 10-3) and SEMA3A (padj = 3.3 × 10-3). Highly downregulated genes in all the SS-3 adenomas included HLA-B (padj = 3.3 × 10-6), suggesting reduced antigen presentation by the adenoma to cytotoxic T-cells. Quantitative RT-PCR of these genes performed on the adenoma samples supported the RNAseq results. We also found a relative decrease in the overall concentration of T-lymphocytes in the SS-3 tumors. These results suggest that SS-3 adenomas actively suppress the immune system and raise the possibility that they may be treatable with immune checkpoint inhibitors or nonspecific cancer immunotherapies.",
keywords = "ARG2, HLA-B, Null cell adenoma, Pituitary adenoma, SEMA3A, Silent subtype III, Transcriptome sequencing",
author = "Richardson, {Timothy E.} and Shen, {Zhong Jian} and Mohammed Kanchwala and Chao Xing and Alexander Filatenkov and Ping Shang and Samuel Barnett and Zahidur Abedin and Malter, {James S.} and Raisanen, {Jack M.} and Burns, {Dennis K.} and White, {Charles L.} and Hatanpaa, {Kimmo J.}",
year = "2017",
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T1 - Aggressive Behavior in Silent Subtype III Pituitary Adenomas May Depend on Suppression of Local Immune Response

T2 - A Whole Transcriptome Analysis

AU - Richardson, Timothy E.

AU - Shen, Zhong Jian

AU - Kanchwala, Mohammed

AU - Xing, Chao

AU - Filatenkov, Alexander

AU - Shang, Ping

AU - Barnett, Samuel

AU - Abedin, Zahidur

AU - Malter, James S.

AU - Raisanen, Jack M.

AU - Burns, Dennis K.

AU - White, Charles L.

AU - Hatanpaa, Kimmo J.

PY - 2017/10/1

Y1 - 2017/10/1

N2 - Silent subtype III pituitary adenomas (SS-3) are clinically nonfunctional adenomas that are more aggressive in terms of invasion and risk of recurrence than their conventional null cell counterparts. We previously showed that these tumors can be distinguished by immunohistochemistry based on the identification of a markedly enlarged and fragmented Golgi apparatus. To understand the molecular correlates of differential aggressiveness, we performed whole transcriptome sequencing (RNAseq) on 4 SS-3 and 4 conventional null cell adenomas. The genes that were highly upregulated in all the SS-3 adenomas included 2 secreted proteins involved in the suppression of T-lymphocyte activity, i.e., ARG2 (multiple testing adjusted padj = 1.5 × 10-3) and SEMA3A (padj = 3.3 × 10-3). Highly downregulated genes in all the SS-3 adenomas included HLA-B (padj = 3.3 × 10-6), suggesting reduced antigen presentation by the adenoma to cytotoxic T-cells. Quantitative RT-PCR of these genes performed on the adenoma samples supported the RNAseq results. We also found a relative decrease in the overall concentration of T-lymphocytes in the SS-3 tumors. These results suggest that SS-3 adenomas actively suppress the immune system and raise the possibility that they may be treatable with immune checkpoint inhibitors or nonspecific cancer immunotherapies.

AB - Silent subtype III pituitary adenomas (SS-3) are clinically nonfunctional adenomas that are more aggressive in terms of invasion and risk of recurrence than their conventional null cell counterparts. We previously showed that these tumors can be distinguished by immunohistochemistry based on the identification of a markedly enlarged and fragmented Golgi apparatus. To understand the molecular correlates of differential aggressiveness, we performed whole transcriptome sequencing (RNAseq) on 4 SS-3 and 4 conventional null cell adenomas. The genes that were highly upregulated in all the SS-3 adenomas included 2 secreted proteins involved in the suppression of T-lymphocyte activity, i.e., ARG2 (multiple testing adjusted padj = 1.5 × 10-3) and SEMA3A (padj = 3.3 × 10-3). Highly downregulated genes in all the SS-3 adenomas included HLA-B (padj = 3.3 × 10-6), suggesting reduced antigen presentation by the adenoma to cytotoxic T-cells. Quantitative RT-PCR of these genes performed on the adenoma samples supported the RNAseq results. We also found a relative decrease in the overall concentration of T-lymphocytes in the SS-3 tumors. These results suggest that SS-3 adenomas actively suppress the immune system and raise the possibility that they may be treatable with immune checkpoint inhibitors or nonspecific cancer immunotherapies.

KW - ARG2

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