Preferential expansion of pro-inflammatory Tregs in human non-small cell lung cancer

Joseph D. Phillips, Lawrence M. Knab*, Nichole R. Blatner, Leila Haghi, Malcom McAvoy DeCamp Jr, Shari Lynn Meyerson, Michael J. Heiferman, Jeffrey R. Heiferman, Fotini Gounari, David Jason Bentrem, Khashayarsha Khazaie

*Corresponding author for this work

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Objectives: Lung cancer is the leading cause of cancer-related death in the USA. Regulatory T cells (Tregs) normally function to temper immune responses and decrease inflammation. Previous research has demonstrated different subsets of Tregs with contrasting anti- or pro-inflammatory properties. This study aimed to determine Treg subset distributions and characteristics present in non-small cell lung cancer (NSCLC) patients. Methods: Peripheral blood was collected from healthy controls (HC) and NSCLC patients preceding surgical resection, and mononuclear cells were isolated, stained, and analyzed by flow cytometry. Tregs were defined by expression of CD4 and CD25 and classified into CD45RA+Foxp3int (naïve, Fr. I) or CD45RAFoxp3hi (activated Fr. II). Activated conventional T cells were CD4+CD45RAFoxp3int (Fr. III). Results: Samples from 23 HC and 26 NSCLC patients were collected. Tregs isolated from patients with NSCLC were found to have enhanced suppressive function on naive T cells. Cancer patients had significantly increased frequencies of activated Tregs (fraction II: FrII), 17.5 versus 3.2 % (P < 0.001). FrII Tregs demonstrated increased RORγt and IL17 expression and decreased IL10 expression compared to Tregs from HC, indicating pro-inflammatory characteristics. Conclusions: This study demonstrates that a novel subset of Tregs with pro-inflammatory characteristics preferentially expand in NSCLC patients. This Treg subset appears identical to previously reported pro-inflammatory Tregs in human colon cancer patients and in mouse models of polyposis. We expect the pro-inflammatory Tregs in lung cancer to contribute to the immune pathogenesis of disease and propose that targeting this Treg subset may have protective benefits in NSCLC.

Original languageEnglish (US)
Pages (from-to)1185-1191
Number of pages7
JournalCancer Immunology, Immunotherapy
Volume64
Issue number9
DOIs
StatePublished - Sep 21 2015

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Non-Small Cell Lung Carcinoma
Lung Neoplasms
T-Lymphocytes
Immune System Diseases
Regulatory T-Lymphocytes
Interleukin-10
Colonic Neoplasms
Neoplasms
Flow Cytometry
Anti-Inflammatory Agents
Inflammation
Research

Keywords

  • Inflammation
  • Lung cancer
  • Regulatory T cells
  • T helper 17 cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Oncology
  • Cancer Research

Cite this

Phillips, J. D., Knab, L. M., Blatner, N. R., Haghi, L., DeCamp Jr, M. M., Meyerson, S. L., ... Khazaie, K. (2015). Preferential expansion of pro-inflammatory Tregs in human non-small cell lung cancer. Cancer Immunology, Immunotherapy, 64(9), 1185-1191. https://doi.org/10.1007/s00262-015-1725-1
Phillips, Joseph D. ; Knab, Lawrence M. ; Blatner, Nichole R. ; Haghi, Leila ; DeCamp Jr, Malcom McAvoy ; Meyerson, Shari Lynn ; Heiferman, Michael J. ; Heiferman, Jeffrey R. ; Gounari, Fotini ; Bentrem, David Jason ; Khazaie, Khashayarsha. / Preferential expansion of pro-inflammatory Tregs in human non-small cell lung cancer. In: Cancer Immunology, Immunotherapy. 2015 ; Vol. 64, No. 9. pp. 1185-1191.
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title = "Preferential expansion of pro-inflammatory Tregs in human non-small cell lung cancer",
abstract = "Objectives: Lung cancer is the leading cause of cancer-related death in the USA. Regulatory T cells (Tregs) normally function to temper immune responses and decrease inflammation. Previous research has demonstrated different subsets of Tregs with contrasting anti- or pro-inflammatory properties. This study aimed to determine Treg subset distributions and characteristics present in non-small cell lung cancer (NSCLC) patients. Methods: Peripheral blood was collected from healthy controls (HC) and NSCLC patients preceding surgical resection, and mononuclear cells were isolated, stained, and analyzed by flow cytometry. Tregs were defined by expression of CD4 and CD25 and classified into CD45RA+Foxp3int (na{\"i}ve, Fr. I) or CD45RA−Foxp3hi (activated Fr. II). Activated conventional T cells were CD4+CD45RA−Foxp3int (Fr. III). Results: Samples from 23 HC and 26 NSCLC patients were collected. Tregs isolated from patients with NSCLC were found to have enhanced suppressive function on naive T cells. Cancer patients had significantly increased frequencies of activated Tregs (fraction II: FrII), 17.5 versus 3.2 {\%} (P < 0.001). FrII Tregs demonstrated increased RORγt and IL17 expression and decreased IL10 expression compared to Tregs from HC, indicating pro-inflammatory characteristics. Conclusions: This study demonstrates that a novel subset of Tregs with pro-inflammatory characteristics preferentially expand in NSCLC patients. This Treg subset appears identical to previously reported pro-inflammatory Tregs in human colon cancer patients and in mouse models of polyposis. We expect the pro-inflammatory Tregs in lung cancer to contribute to the immune pathogenesis of disease and propose that targeting this Treg subset may have protective benefits in NSCLC.",
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Phillips, JD, Knab, LM, Blatner, NR, Haghi, L, DeCamp Jr, MM, Meyerson, SL, Heiferman, MJ, Heiferman, JR, Gounari, F, Bentrem, DJ & Khazaie, K 2015, 'Preferential expansion of pro-inflammatory Tregs in human non-small cell lung cancer', Cancer Immunology, Immunotherapy, vol. 64, no. 9, pp. 1185-1191. https://doi.org/10.1007/s00262-015-1725-1

Preferential expansion of pro-inflammatory Tregs in human non-small cell lung cancer. / Phillips, Joseph D.; Knab, Lawrence M.; Blatner, Nichole R.; Haghi, Leila; DeCamp Jr, Malcom McAvoy; Meyerson, Shari Lynn; Heiferman, Michael J.; Heiferman, Jeffrey R.; Gounari, Fotini; Bentrem, David Jason; Khazaie, Khashayarsha.

In: Cancer Immunology, Immunotherapy, Vol. 64, No. 9, 21.09.2015, p. 1185-1191.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Preferential expansion of pro-inflammatory Tregs in human non-small cell lung cancer

AU - Phillips, Joseph D.

AU - Knab, Lawrence M.

AU - Blatner, Nichole R.

AU - Haghi, Leila

AU - DeCamp Jr, Malcom McAvoy

AU - Meyerson, Shari Lynn

AU - Heiferman, Michael J.

AU - Heiferman, Jeffrey R.

AU - Gounari, Fotini

AU - Bentrem, David Jason

AU - Khazaie, Khashayarsha

PY - 2015/9/21

Y1 - 2015/9/21

N2 - Objectives: Lung cancer is the leading cause of cancer-related death in the USA. Regulatory T cells (Tregs) normally function to temper immune responses and decrease inflammation. Previous research has demonstrated different subsets of Tregs with contrasting anti- or pro-inflammatory properties. This study aimed to determine Treg subset distributions and characteristics present in non-small cell lung cancer (NSCLC) patients. Methods: Peripheral blood was collected from healthy controls (HC) and NSCLC patients preceding surgical resection, and mononuclear cells were isolated, stained, and analyzed by flow cytometry. Tregs were defined by expression of CD4 and CD25 and classified into CD45RA+Foxp3int (naïve, Fr. I) or CD45RA−Foxp3hi (activated Fr. II). Activated conventional T cells were CD4+CD45RA−Foxp3int (Fr. III). Results: Samples from 23 HC and 26 NSCLC patients were collected. Tregs isolated from patients with NSCLC were found to have enhanced suppressive function on naive T cells. Cancer patients had significantly increased frequencies of activated Tregs (fraction II: FrII), 17.5 versus 3.2 % (P < 0.001). FrII Tregs demonstrated increased RORγt and IL17 expression and decreased IL10 expression compared to Tregs from HC, indicating pro-inflammatory characteristics. Conclusions: This study demonstrates that a novel subset of Tregs with pro-inflammatory characteristics preferentially expand in NSCLC patients. This Treg subset appears identical to previously reported pro-inflammatory Tregs in human colon cancer patients and in mouse models of polyposis. We expect the pro-inflammatory Tregs in lung cancer to contribute to the immune pathogenesis of disease and propose that targeting this Treg subset may have protective benefits in NSCLC.

AB - Objectives: Lung cancer is the leading cause of cancer-related death in the USA. Regulatory T cells (Tregs) normally function to temper immune responses and decrease inflammation. Previous research has demonstrated different subsets of Tregs with contrasting anti- or pro-inflammatory properties. This study aimed to determine Treg subset distributions and characteristics present in non-small cell lung cancer (NSCLC) patients. Methods: Peripheral blood was collected from healthy controls (HC) and NSCLC patients preceding surgical resection, and mononuclear cells were isolated, stained, and analyzed by flow cytometry. Tregs were defined by expression of CD4 and CD25 and classified into CD45RA+Foxp3int (naïve, Fr. I) or CD45RA−Foxp3hi (activated Fr. II). Activated conventional T cells were CD4+CD45RA−Foxp3int (Fr. III). Results: Samples from 23 HC and 26 NSCLC patients were collected. Tregs isolated from patients with NSCLC were found to have enhanced suppressive function on naive T cells. Cancer patients had significantly increased frequencies of activated Tregs (fraction II: FrII), 17.5 versus 3.2 % (P < 0.001). FrII Tregs demonstrated increased RORγt and IL17 expression and decreased IL10 expression compared to Tregs from HC, indicating pro-inflammatory characteristics. Conclusions: This study demonstrates that a novel subset of Tregs with pro-inflammatory characteristics preferentially expand in NSCLC patients. This Treg subset appears identical to previously reported pro-inflammatory Tregs in human colon cancer patients and in mouse models of polyposis. We expect the pro-inflammatory Tregs in lung cancer to contribute to the immune pathogenesis of disease and propose that targeting this Treg subset may have protective benefits in NSCLC.

KW - Inflammation

KW - Lung cancer

KW - Regulatory T cells

KW - T helper 17 cells

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Phillips JD, Knab LM, Blatner NR, Haghi L, DeCamp Jr MM, Meyerson SL et al. Preferential expansion of pro-inflammatory Tregs in human non-small cell lung cancer. Cancer Immunology, Immunotherapy. 2015 Sep 21;64(9):1185-1191. https://doi.org/10.1007/s00262-015-1725-1