The immune microenvironment in young patients with triple negative breast cancer

Abstract

Introduction: Triple negative breast cancers (TNBC) are high grade tumours, with poorer disease specific survival. Following diagnosis of metastatic disease, survival is typically short and novel treatment strategies are required. The immune system is increasingly recognised to play an important role in TNBC biology; the tumour microenvironment (TME) is central to immune evasion. I explored the interaction between the TME, immunogenicity and prognosis in a cohort of young women with TNBC. Methods: The POSH study is a prospective observational study of almost 3000 patients aged 40 years or younger with a first diagnosis of invasive breast cancer. Associations between clinicopathological features and molecular markers (using tissue microarrays) and prognosis were assessed in those with TNBC. These factors were integrated into a prognostic score using ROC analysis. Correlates of immune activity were identified and digital pathology analyses utilised. Murine breast fibroblasts were differentiated into the myofibroblastic phenotype in vitro, with qtPCR, western blot, cell count, immunofluorescence and metabolism assays performed. The effect of myofibroblast co injection on tumour growth using the 4T1 model in vivo was studied. Finally, AZD0156, a novel cancer associated fibroblast (CAF) inhibitor, was assessed for efficacy and compared to immunotherapy in vivo. Results: Tumour infiltrating lymphocyte (TIL) density was highly prognostic and was significantly higher in those with a germline BRCA mutation. Bioinformatics of publically available datasets revealed that extracellular matrix pathways were upregulated in lymphocyte deplete TNBC cases. An inverse correlation between smooth muscle actin (SMA) and TIL was found. Murine breast fibroblasts were transformed in vitro using TGF β; myofibroblasts augmented tumour growth in a TNBC murine model. An ATM inhibitor (AZD0156) inhibited the myofibroblastic phenotype and was effective at reducing tumour growth using the CAF rich 4T1 model in vivo. This effect was not mediated via CD8 infiltration but there was a reduction in CAF density. Conclusion: The TME is an important factor in immune evasion in TNBC. CAF inhibition may be an effective treatment strategy and should be investigated in combination with other agents.

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