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Title: Breast cancer and the immune system : the response of lymphocytes to breast cancer and to chemotherapy
Author: Verma, Rashmi
ISNI:       0000 0004 7657 0173
Awarding Body: University of Leeds
Current Institution: University of Leeds
Date of Award: 2018
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Background and Aim: Chemotherapy is used for treatment of breast cancer. However, relatively little is known about the extent or the time course of immune dysfunction caused by it. The aim of this study was to evaluate the circulating lymphocytes and tetanus & pneumococcal antibody titers pre and at various time points post-chemotherapy and check for association between circulating lymphocytes and tumour infiltrating lymphocytes (TILs) and their correlations with patient outcome. Methods: Detailed immunophenotyping of peripheral blood lymphocytes was performed by flow cytometry in 88 patients with primary breast cancer before and at various time points up to 9 months after chemotherapy. Peripheral blood levels of anti-pneumococcal and anti-tetanus antibodies were assessed using ELISA. Immunohistochemistry was used to assess the presence of tumour infiltrating CD20+, CD4+, CD8+ and FoxP3+ positive lymphocytes in the tumour microenvironment. Results: There were significant depletions of circulating B, CD4+T, CD8+T and NK cells at 2 weeks post-chemotherapy (p < 0.001), with B cells showing maximum depletion. Levels of B cells and CD4+ T cells remained significantly low even at 9 months post-chemotherapy (p < 0.001). Repopulating B and CD4+ T cell phenotypes were different from the pre-chemotherapy profile. Titers of anti-pneumococcal and anti-tetanus antibodies were significantly reduced post- chemotherapy and did not return to normal even at 9 months post-chemotherapy (p < 0.001). Smoking and chemotherapy regimen had significant correlations with degrees of depletion and repopulation of B and T cells. Chemotherapy regimen and the extent of depletion of lymphocytes had a significant influence on overall and disease-free survival. Analysis of TILs showed significant correlations between the stromal and intra-tumoural levels of each of the lymphocytes and between different lymphocytes. TILs correlated with hormone negative, triple negative and grade 3 tumours. Only tumour infiltrating CD8+ lymphocytes correlated with its matched circulating levels, and this positive correlation was stronger in hormone negative and triple negative tumours. High CD4+ stromal infiltrate was associated with better disease-free survival and overall survival. High stromal CD8+ T cells were associated with better disease-free survival in ER/PR negative patients, while high intra-tumoural CD8+ T cell and FoxP3+ infiltrate was associated with poor overall survival in the ER/PR positive cohort. Conclusion: Breast cancer chemotherapy has significant long-term effects on the immune parameters and this should be taken into consideration during clinical management. TILs are associated with poor prognostic features and also show some correlation with circulating lymphocytes. The site and type of lymphocyte infiltrate in the tumour microenvironment influences outcome.
Supervisor: Hughes, Thomas ; Carter, Clive ; Horgan, Kieran Sponsor: Not available
Qualification Name: Thesis (M.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available