Exploring immune interactions in triple negative breast cancer: IL-1β inhibition and its therapeutic potential

Triple negative breast cancer (TNBC) has poor prognosis when compared to other breast cancer subtypes. Despite pre-clinical data supporting an immune targeted approach for TNBCs, immunotherapy has failed to demonstrate the impressive responses seen in other solid tumor malignancies. Additional strategies to modify the tumor immune microenvironment and potentiate response to immunotherapy are needed. In this review, we summarise phase III data supporting the use of immunotherapy for TNBC. We discuss the role of IL-1β in tumorigenesis and summarize pre-clinical data supporting IL-1β inhibition as a potential therapeutic strategy in TNBC. Finally, we present current trials evaluating IL-1β in breast cancer and other solid tumor malignancies and discuss future studies that may provide a strong scientific rationale for the combination of IL-1β and immunotherapy in the neoadjuvant and metastatic setting for people with TNBC.

[1]  A. Ardizzoni,et al.  LBA49 CANOPY-A: Phase III study of canakinumab (CAN) as adjuvant therapy in patients (pts) with completely resected non-small cell lung cancer (NSCLC) , 2022, Annals of Oncology.

[2]  T. Jacks,et al.  LBA1 Mechanism of action and an actionable inflammatory axis for air pollution induced non-small cell lung cancer: Towards molecular cancer prevention , 2022, Annals of Oncology.

[3]  S. Loi,et al.  Pembrolizumab plus Chemotherapy in Advanced Triple-Negative Breast Cancer. , 2022, The New England journal of medicine.

[4]  P. Fasching,et al.  Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. , 2022, The New England journal of medicine.

[5]  N. Donato,et al.  Therapeutic inhibition of USP9x-mediated Notch signaling in triple-negative breast cancer , 2021, Proceedings of the National Academy of Sciences.

[6]  B. Halmos,et al.  1194MO Canakinumab (CAN) + docetaxel (DTX) for the second- or third-line (2/3L) treatment of advanced non-small cell lung cancer (NSCLC): CANOPY-2 phase III results , 2021, Annals of Oncology.

[7]  V. Tripathi,et al.  An updated review on the role of the CXCL8-CXCR1/2 axis in the progression and metastasis of breast cancer , 2021, Molecular Biology Reports.

[8]  W. Weichert,et al.  Outcome of breast cancer patients with low hormone receptor positivity: Analysis of a 15-year population-based cohort. , 2021, Annals of oncology : official journal of the European Society for Medical Oncology.

[9]  M. Dieci,et al.  Impact of estrogen receptor levels on outcome in non-metastatic triple negative breast cancer patients treated with neoadjuvant/adjuvant chemotherapy , 2021, NPJ breast cancer.

[10]  A. Schneeweiss,et al.  First-line atezolizumab plus nab-paclitaxel for unresectable, locally advanced, or metastatic triple-negative breast cancer: IMpassion130 final overall survival analysis. , 2021, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  Y. Wang,et al.  Primary results from IMpassion131, a double-blind, placebo-controlled, randomised phase III trial of first-line paclitaxel with or without atezolizumab for unresectable locally advanced/metastatic triple-negative breast cancer. , 2021, Annals of oncology : official journal of the European Society for Medical Oncology.

[12]  Edward S. Kim,et al.  Canakinumab with and without pembrolizumab in patients with resectable non-small-cell lung cancer: CANOPY-N study design. , 2021, Future oncology.

[13]  A. Jemal,et al.  Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries , 2021, CA: a cancer journal for clinicians.

[14]  M. Lauriola,et al.  Roles of IL-1 in Cancer: From Tumor Progression to Resistance to Targeted Therapies , 2020, International journal of molecular sciences.

[15]  B. Cetin,et al.  Pembrolizumab for Early Triple-Negative Breast Cancer. , 2020, The New England journal of medicine.

[16]  P. Fasching,et al.  Pembrolizumab for Early Triple-Negative Breast Cancer. , 2020, The New England journal of medicine.

[17]  C. Perou,et al.  Estrogen and Progesterone Receptor Testing in Breast Cancer: ASCO/CAP Guideline Update. , 2020, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  Ahmedin Jemal,et al.  Breast cancer statistics, 2019 , 2019, CA: a cancer journal for clinicians.

[19]  D. Philpott,et al.  Canonical and noncanonical inflammasomes in intestinal epithelial cells , 2019, Cellular microbiology.

[20]  E. Brint,et al.  IL-1 Family Members in Cancer; Two Sides to Every Story , 2019, Front. Immunol..

[21]  A. Dzutsev,et al.  Cell‐Type‐Specific Responses to Interleukin‐1 Control Microbial Invasion and Tumor‐Elicited Inflammation in Colorectal Cancer , 2019, Immunity.

[22]  Y. Carmi,et al.  Blocking IL-1β reverses the immunosuppression in mouse breast cancer and synergizes with anti–PD-1 for tumor abrogation , 2018, Proceedings of the National Academy of Sciences.

[23]  E. Winer,et al.  Atezolizumab and Nab‐Paclitaxel in Advanced Triple‐Negative Breast Cancer , 2018, The New England journal of medicine.

[24]  John N. Hutchinson,et al.  IL-1β inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization , 2018, Nature Cell Biology.

[25]  C. Denkert,et al.  Tumor infiltrating lymphocytes in early breast cancer. , 2018, Breast.

[26]  T. Kanneganti,et al.  Function and regulation of IL‐1α in inflammatory diseases and cancer , 2018, Immunological reviews.

[27]  R. Collins,et al.  Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial , 2017, The Lancet.

[28]  H. Berman,et al.  Notch Shapes the Innate Immunophenotype in Breast Cancer. , 2017, Cancer discovery.

[29]  Stewart G. Martin,et al.  Macrophage-derived interleukin-1beta promotes human breast cancer cell migration and lymphatic adhesion in vitro , 2017, Cancer Immunology, Immunotherapy.

[30]  Zihai Li,et al.  Targeting inflammasome/IL-1 pathways for cancer immunotherapy , 2016, Scientific Reports.

[31]  S. Adams,et al.  Variation in the Incidence and Magnitude of Tumor-Infiltrating Lymphocytes in Breast Cancer Subtypes: A Systematic Review. , 2016, JAMA oncology.

[32]  I. Holen,et al.  IL-1 drives breast cancer growth and bone metastasis in vivo , 2016, Oncotarget.

[33]  M. Seo,et al.  IL-1β induces IL-6 production and increases invasiveness and estrogen-independent growth in a TG2-dependent manner in human breast cancer cells , 2016, BMC Cancer.

[34]  M. Seo,et al.  IL-1β induces IL-6 production and increases invasiveness and estrogen-independent growth in a TG2-dependent manner in human breast cancer cells , 2016, BMC Cancer.

[35]  V. Dixit,et al.  Inflammasomes: mechanism of assembly, regulation and signalling , 2016, Nature Reviews Immunology.

[36]  V. Pascual,et al.  Safety and immunologic activity of anakinra in HER2-negative metastatic breast cancer (MBC). , 2016 .

[37]  H. Schmidt,et al.  Immunological correlates of treatment and response in stage IV malignant melanoma patients treated with Ipilimumab , 2016, Oncoimmunology.

[38]  Carsten Denkert,et al.  Clinical relevance of host immunity in breast cancer: from TILs to the clinic , 2016, Nature Reviews Clinical Oncology.

[39]  I. Fernández,et al.  Tumor-Infiltrating Lymphocytes in Triple Negative Breast Cancer: The Future of Immune Targeting , 2016, Clinical Medicine Insights. Oncology.

[40]  Jedd D. Wolchok,et al.  The future of cancer treatment: immunomodulation, CARs and combination immunotherapy , 2016, Nature Reviews Clinical Oncology.

[41]  I. Filippi,et al.  Interleukin-1β Affects MDAMB231 Breast Cancer Cell Migration under Hypoxia: Role of HIF-1α and NFκB Transcription Factors , 2015, Mediators of inflammation.

[42]  Molin Wang,et al.  Prognostic value of tumor-infiltrating lymphocytes in triple-negative breast cancers from two phase III randomized adjuvant breast cancer trials: ECOG 2197 and ECOG 1199. , 2014, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[43]  Jeffrey W Pollard,et al.  Tumor-associated macrophages: from mechanisms to therapy. , 2014, Immunity.

[44]  I. Holen,et al.  Different molecular profiles are associated with breast cancer cell homing compared with colonisation of bone: evidence using a novel bone-seeking cell line. , 2014, Endocrine-related cancer.

[45]  Y. Carmi,et al.  The role IL-1 in tumor-mediated angiogenesis , 2014, Front. Physiol..

[46]  C. Meyer,et al.  Frequencies of circulating MDSC correlate with clinical outcome of melanoma patients treated with ipilimumab , 2014, Cancer Immunology, Immunotherapy.

[47]  S. Cramer,et al.  A Role for Interleukin-1 Alpha in the 1,25 Dihydroxyvitamin D3 Response in Mammary Epithelial Cells , 2013, PloS one.

[48]  H. Schreiber,et al.  Innate and adaptive immune cells in the tumor microenvironment , 2013, Nature Immunology.

[49]  Stefan Michiels,et al.  Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. , 2013, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[50]  A. Palucka,et al.  Neutralizing Tumor-Promoting Chronic Inflammation: A Magic Bullet? , 2013, Science.

[51]  Wei Liu,et al.  Epidermal growth factor (EGF) and interleukin (IL)-1β synergistically promote ERK1/2-mediated invasive breast ductal cancer cell migration and invasion , 2012, Molecular Cancer.

[52]  R. Wenstrup,et al.  Prevalence of BRCA mutations in an unselected population of triple‐negative breast cancer , 2012, Cancer.

[53]  I. Ellis,et al.  Tumour-infiltrating macrophages and clinical outcome in breast cancer , 2011, Journal of Clinical Pathology.

[54]  G. López-Castejón,et al.  Understanding the mechanism of IL-1β secretion , 2011, Cytokine & growth factor reviews.

[55]  T. Meshel,et al.  Inflammatory mediators in breast cancer: Coordinated expression of TNFα & IL-1β with CCL2 & CCL5 and effects on epithelial-to-mesenchymal transition , 2011, BMC Cancer.

[56]  I. Filippi,et al.  Interleukin-1β regulates the migratory potential of MDAMB231 breast cancer cells through the hypoxia-inducible factor-1α. , 2010, European journal of cancer.

[57]  Michael C. Schmid,et al.  Myeloid Cells in the Tumor Microenvironment: Modulation of Tumor Angiogenesis and Tumor Inflammation , 2010, Journal of oncology.

[58]  C. Dinarello Why not treat human cancer with interleukin-1 blockade? , 2010, Cancer and Metastasis Reviews.

[59]  Carsten Denkert,et al.  Tumor-associated lymphocytes as an independent predictor of response to neoadjuvant chemotherapy in breast cancer. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[60]  Y. Carmi,et al.  The Role of Macrophage-Derived IL-1 in Induction and Maintenance of Angiogenesis1 , 2009, The Journal of Immunology.

[61]  L. Coussens,et al.  CD4(+) T cells regulate pulmonary metastasis of mammary carcinomas by enhancing protumor properties of macrophages. , 2009, Cancer cell.

[62]  G. Bhagat,et al.  Overexpression of interleukin-1beta induces gastric inflammation and cancer and mobilizes myeloid-derived suppressor cells in mice. , 2008, Cancer cell.

[63]  T. Stein,et al.  Microenvironment of the Involuting Mammary Gland Mediates Mammary Cancer Progression , 2007, Journal of Mammary Gland Biology and Neoplasia.

[64]  Yoichiro Iwakura,et al.  Interleukin-1beta-driven inflammation promotes the development and invasiveness of chemical carcinogen-induced tumors. , 2007, Cancer research.

[65]  M. Miyazaki,et al.  CCL17 and IL-10 as Effectors That Enable Alternatively Activated Macrophages to Inhibit the Generation of Classically Activated Macrophages1 , 2004, The Journal of Immunology.

[66]  F. Martinon,et al.  The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. , 2002, Molecular cell.

[67]  B. Bresnihan,et al.  The effects of treatment with interleukin-1 receptor antagonist on the inflamed synovial membrane in rheumatoid arthritis. , 2001, Rheumatology.

[68]  A. Jemal,et al.  Breast Cancer Statistics , 2013 .

[69]  K. O. Elliston,et al.  A novel heterodimeric cysteine protease is required for interleukin-1βprocessing in monocytes , 1992, Nature.