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

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). IL1β orchestrates tumor-promoting inflammation in breast cancer and can be targeted in patients using an IL1 receptor antagonist. .

An Interleukin-1 Signature in Breast Cancer Treated with Interleukin-1 Receptor Blockade: Implications for Treating Cytokine Release Syndrome of Checkpoint Inhibitors

“…In reducing IL1α and IL1 β, anakinra will reduce the immunosuppression from myeloid-derived suppressor cells (8). IL1α induction of IL1β is an example of autoinflammation and, as reported in the study, patients with autoinflammatory diseases exhibit the same IL1β signature as patients with breast cancer (1). Myeloid cells in the tumor microenvironment are also a source of growth factors for tumors.…”

“…The study reported in this issue of Cancer Research makes a significant contribution to the concept that inflammation in cancer is driven by IL1β and identified an “IL1 signature” in women with HER2-negative breast cancer (1). The study represents several years of dedicated research on cancer by Palucka and colleagues.…”

“…During the pilot trial, anakinra treatment at any timepoint also resulted in decreased expression of five members of the Toll-Like Receptor (TLR) family. In contrast to the suppression of the TLR and IL1β families by anakinra, increased expression of several natural killer cell and cytotoxic T-cell genes that favor immune-mediated tumor destruction was observed (1). The take home message from the comprehensive Wu and colleagues’ study is the identification of high-risk HER2-negative patients who would benefit from reducing IL1β.…”

“…However, unlike IL1β, the IL1α precursor is biologically active either when expressed as an integral membrane protein or when released upon cell death. IL1α was present in the supernatants of 149 primary cultured breast cancer tissues stimulated with PMA and ionomycin (1). Using coculture of breast cancer cells with myeloid cells, membrane TGFβ was identified as an inducer of the caspase-1–dependent secretion of IL1β.…”

“…Similar to the trial of anti-IL1α in patients with metastatic colorectal cancer (9), some patients with breast cancer reported reduced pain and increased quality of life on anakinra plus chemotherapy and in other studies, anakinra reduced the “sickness syndromes” of chemotherapy used to treat metastatic colorectal cancer but also increased overall survival (3). Three of the 11 patients in the Palucka trial are still alive (1). …”