Abstract
Background: Interactions between the immune system and tumors are highly reciprocal in nature, leading to speculation that tumor recurrence or therapeutic resistance could be influenced or predicted by immune events that manifest locally, but can be detected systemically.Methods: Multi-parameter flow cytometry was used to examine the percentage and phenotype of natural killer (NK) cells, myeloid-derived suppressor cells (MDSCs), monocyte subsets and regulatory T (Treg) cells in the peripheral blood of of 85 patients with breast cancer (50 of whom were assessed before and after one cycle of anthracycline-based chemotherapy), and 23 controls. Transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) in 23 patients were generated using a NanoString gene profiling platform.Results: An increased percentage of immunosuppressive cells such as granulocytic MDSCs, intermediate CD14++CD16+ monocytes and CD127negCD25highFoxP3+ Treg cells was observed in patients with breast cancer, especially patients with stage 3 and 4 disease, regardless of ER status. Following neoadjuvant chemotherapy, B cell numbers decreased significantly, whereas monocyte numbers increased. Although chemotherapy had no effect on the percentage of Treg, MDSC and NK cells, the expression of inhibitory receptors CD85j, LIAR and NKG2A and activating receptors NKp30 and NKp44 on NK cells increased, concomitant with a decreased expression of NKp46 and DNAM-1 activating receptors. Transcriptomic profiling revealed a distinct group of 3 patients in the triple negative breast cancer (TNBC) cohort who expressed high levels of mRNA encoding genes predominantly involved in inflammation. The analysis of a large transcriptomic dataset derived from the tumors of patients with TNBC revealed that the expression of CD163, CXCR4, THBS1 predicted relapse-free survival.Conclusions: The peripheral blood immunome of patients with breast cancer is influenced by the presence and stage of cancer, but not by molecular subtypes. Furthermore, immune profiling coupled with transcriptomic analyses of peripheral blood cells may identify patients with TNBC that are at risk of relapse after chemotherapy.
Highlights
Breast cancer accounts for approximately 15% of all cancers and remains the most common and leading cause of cancer deaths in European women [1]
We investigated [1] whether the peripheral blood immunome of breast cancer patients differs from that of healthy controls; [2] whether chemotherapy affects this immune phenotype; and [3] whether a defined peripheral blood immune phenotypic profile relates to a specific molecular breast cancer subgroup
CD39 expression has previously been shown to be restricted to a subset of FoxP3+ regulatory effector/memory-like T (TREM) cells, whereas ICOS is a CD28-like co-stimulatory molecule which is expressed by recently-activated T cells [13]
Summary
Breast cancer accounts for approximately 15% of all cancers and remains the most common and leading cause of cancer deaths in European women [1]. The observation that patients with TNBC showing more than 50% lymphocytic infiltration in their tumor core, or within the stroma, exhibit a better prognosis indicates the strong influence of the immune system on disease outcomes [2]. Whether the favorable clinical outcome observed in this patient subgroup is related to an inherent ability of the patient to respond to treatment, the quality of the anti-tumor immune response, the functional orientation of the cell infiltrate generated, and/or the immunoregulatory nature of the tumor microenvironment, remains a matter of debate. Interactions between the immune system and tumors are highly reciprocal in nature, leading to speculation that tumor recurrence or therapeutic resistance could be influenced or predicted by immune events that manifest locally, but can be detected systemically
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