Mahmoud, Sahar
(2011)
Inflammation and immunosurveillance in breast cancer.
PhD thesis, University of Nottingham.
Abstract
Breast carcinomas are often infiltrated by inflammatory cells, particularly macrophages and T-lymphocytes but the significance of these cells remains unclear. Potential roles include an immune response against the tumour, and pro-tumour effects such as the release of angiogenic factors or proteolytic enzymes. Breast cancer is a remarkably heterogeneous disease embracing a wide range of clinical patterns, stages of presentation, biological behaviour,prognostic characteristics and response to different types of treatment.International efforts have been made to improve survival rate by early diagnosis and multiple therapies. However, the limitations of the current therapeutic modalities have led to increasing enthusiasm for defining new prognostic tools and developing highly targeted therapies.
The main aim of this thesis was to examine the characteristics of different components of innate and adaptive immune cells infiltrating breast carcinomas utilising a large cohorts of cases (n= 1902) including various histological and biological subtypes to determine the individual role for each component of breast cancer inflammatory cell infiltrate in disease progression. To this end, in situ immunohistochemical analyses were conducted on breast cancer tissue microarrays (TMAs) using monoclonal antibodies against T-cell, B-cell, macrophage, NK and dendritic cell markers. The interactions between the multiple cells in the tumour microenvironment were subsequently assessed using a powerful bioinformatics tool with the aim of classifying breast carcinomas into prognostic subgroups using multiple phenotypes of infiltrating immune/inflammatory cells.
The results of this thesis have demonstrated that phenotype, in addition to the quantity, of tumour-infiltrating lymphocytes is a critical determinant for patient prognosis. In situ cytotoxic T lymphocytic infiltration was associated with a better prognosis independent of standard factors (HR= 0.58, 95% CI= 0.45 0.73, p< 0.001), suggesting that the cell mediated immune response is important in breast cancer. Furthermore, humoral immunity, investigated by the CD20 marker, had an independent prognostic role (HR= 0.75, 95% CI= 0.58-0.96, p= 0.025). The current study has also suggested that macrophage populations do not have a vital role in breast cancer patients’ survival but supported the previously described pro-tumour role played by macrophages in a large cohort. Furthermore, the present study has shown a scant number of dendritic cells infiltrating breast carcinomas.
In general, infiltrating leucocytes have preferentially accumulated within the stromal elements away from tumour islands with less observed infiltration within tumour cell nests and this may be due to the higher concentration of chemoattractants in the stroma and/or inhibitory cytokines produced by tumour cells. Moreover, higher levels of inflammatory-cell infiltrate have correlated with higher tumour grade which could be explained by the higher levels of ‘dangerous signals’ in these tumours. The current study has determined a class of tumours that demonstrates higher levels of inflammatory cell infiltrate associated with a better prognosis, suggesting that the immune effects of the inflammation predominate over the pro-tumour effects, despite immunoediting. The present thesis has introduced into literature robust evidence which support the previous proposal to consider the immune reaction as the seventh hallmark of cancer.
In conclusion, this thesis proposes an immune scoring based on the phenotype, count, and localisation of leucocytic infiltrates as a novel prognostic factor in breast cancer, in addition to currently available factors to aid in decisions regarding new modalities of immunotherapy. More studies are warranted to translate the histopathological and molecular investigation into clinical management of breast cancer.
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