IL1 Receptor Antagonist Controls Transcriptional Signature of Inflammation in Patients with Metastatic Breast Cancer

Te-Chia Wu; Kangling Xu; Jan Martinek; Robyn R Young; Romain Banchereau; Joshy George; Jacob Turner; Kyung In Kim; Sandra Zurawski; Xuan Wang; Derek Blankenship; Hannah M Brookes; Florentina Marches; Gerlinde Obermoser; Elizabeth Lavecchio; Maren K Levin; Sookyoung Bae; Cheng-Han Chung; Jennifer L Smith; Alma-Martina Cepika; Kyp L Oxley; George J Snipes; Jacques Banchereau; Virginia Pascual; Joyce O'Shaughnessy; A Karolina Palucka

doi:10.1158/0008-5472.CAN-18-0413

IL1 Receptor Antagonist Controls Transcriptional Signature of Inflammation in Patients with Metastatic Breast Cancer

Cancer Res. 2018 Sep 15;78(18):5243-5258. doi: 10.1158/0008-5472.CAN-18-0413. Epub 2018 Jul 16.

Authors

Te-Chia Wu^#^{1

2}, Kangling Xu^#¹, Jan Martinek^#^{1

2

3}, Robyn R Young⁴, Romain Banchereau¹, Joshy George², Jacob Turner¹, Kyung In Kim², Sandra Zurawski¹, Xuan Wang¹, Derek Blankenship¹, Hannah M Brookes², Florentina Marches^{1

2}, Gerlinde Obermoser¹, Elizabeth Lavecchio¹, Maren K Levin¹, Sookyoung Bae², Cheng-Han Chung^{1

2

3}, Jennifer L Smith¹, Alma-Martina Cepika¹, Kyp L Oxley¹, George J Snipes⁵, Jacques Banchereau^{1

2}, Virginia Pascual¹, Joyce O'Shaughnessy⁶, A Karolina Palucka^{7

2}

Affiliations

¹ Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, Texas.
² The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut.
³ Department of Biomedical Studies, Baylor University, Waco, Texas.
⁴ The Center for Cancer and Blood Disorders, Fort Worth, Texas.
⁵ Baylor University Medical Center, Sammons Cancer Center, Dallas, Texas.
⁶ Baylor University Medical Center, Charles A. Sammons Cancer Center, Texas Oncology, Dallas, Texas.
⁷ Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, Texas. karolina.palucka@jax.org.

^# Contributed equally.

Abstract

Inflammation affects tumor immune surveillance and resistance to therapy. Here, we show that production of IL1β in primary breast cancer tumors is linked with advanced disease and originates from tumor-infiltrating CD11c⁺ myeloid cells. IL1β production is triggered by cancer cell membrane-derived TGFβ. Neutralizing TGFβ or IL1 receptor prevents breast cancer progression in humanized mouse model. Patients with metastatic HER2^- breast cancer display a transcriptional signature of inflammation in the blood leukocytes, which is attenuated after IL1 blockade. When present in primary breast cancer tumors, this signature discriminates patients with poor clinical outcomes in two independent public datasets (TCGA and METABRIC).Significance: IL1β orchestrates tumor-promoting inflammation in breast cancer and can be targeted in patients using an IL1 receptor antagonist. Cancer Res; 78(18); 5243-58. ©2018 AACRSee related commentary by Dinarello, p. 5200.

Publication types

Clinical Trial
Research Support, N.I.H., Extramural

MeSH terms

Animals
Breast Neoplasms / drug therapy
Breast Neoplasms / metabolism*
CD11c Antigen / metabolism
Capecitabine / administration & dosage
Cell Line, Tumor
Cell Membrane / metabolism
Female
Furans / administration & dosage
Gene Expression Regulation, Neoplastic*
Humans
Inflammation
Interleukin 1 Receptor Antagonist Protein / administration & dosage
Interleukin 1 Receptor Antagonist Protein / metabolism*
Interleukin-1beta / metabolism*
Ketones / administration & dosage
Leukocytes, Mononuclear / cytology
Macrophages / metabolism
Mice
Mice, SCID
Myeloid Cells / metabolism
Neoplasm Metastasis
Neoplasm Transplantation
Paclitaxel / administration & dosage
Pilot Projects
Transcription, Genetic*
Transforming Growth Factor beta / metabolism

Substances

CD11c Antigen
Furans
IL1RN protein, human
Interleukin 1 Receptor Antagonist Protein
Interleukin-1beta
Ketones
Transforming Growth Factor beta
Capecitabine
eribulin
Paclitaxel

Grants and funding

P30 CA034196/CA/NCI NIH HHS/United States