Abstract
Triple negative breast cancers (TNBCs) are a morphologically and molecularly heterogeneous group of breast cancers, defined by the absence of estrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor (HER2). Characterised by an aggressive phenotype, high prevalence in younger women and those of African American ethnicity, TNBC represents a significant unmet medical need despite therapeutic advances. These developments in targeted therapies have harnessed the immunogenic nature of TNBCs and subsequent approval in combination with chemotherapy in the adjuvant and metastatic setting. As such, assessment of stromal tumour-infiltrating lymphocytes (sTILs) within TNBCs has shown greater predictive value over classical staging parameters in response to chemotherapy and immunotherapy. Critically, the presence of cancerous cells within the sentinel lymph nodes and the number of metastatic lymph nodes are essential assessment parameters for routine pathological diagnoses. Our group have previously shown the additive prognostic value of immune responses within the tumour- adjacent lymph nodes, in particular germinal centre formation, and their subsequent association with sTIL density, the incidence of tertiary lymphoid structures at the primary tumour and longer distant-metastasis free survival. This thesis therefore aimed to explore the temporal, cellular and spatial immune composition of lymph nodes and the lymph node- tumour crosstalk, utilising several imaging, molecular and in vivo modalities.We harnessed transcriptional analyses of microarray data from TNBC primary tumours and assessed the prognostic Immunophenotyping a pilot study of lymph nodes from two patients with opposing disease trajectories and sTIL scores at the primary tumour revealed a reduction in PD1+T cell populations potentially influencing germinal centre responses, and upregulation of immunosuppressive subsets with distinct spatial properties within the lymph node. A wider exploration of molecular data of these subsets defined a subgroup of immunologically cold TNBCs with increased plasma cell infiltration; low sTILs, high plasma (lThP), exhibiting features of the luminal androgen receptor subtype and shorter time to distant metastasis.
The spatial orientation and infiltration of plasma cells within the tumour and lymph node were subsequently validated within an independent cohort of high-risk low sTILs TNBC patients.
I further utilised four distinct mouse models of TNBC with a range of metastatic abilities, to study for the first time, the temporal characteristics of germinal centre development in response to nearby tumour growth. This revealed differences in the kinetic features of the germinal centre B cell response within the tumour draining lymph nodes, and the phenotype of memory B and plasma cell subsets generated in response to the developing tumour.
To elucidate potential mechanisms that may be impacting germinal centre formation and plasma cell production in lymph nodes, I subsequently focussed on the IGF1 pathway. This revealed that overexpression of IGF1 promoted tumour growth in vitro and in vivo, dampened germinal centre responses and promoted an IgM+ plasma cell phenotype.
Overall, this thesis provides new insights into the molecular features of a subgroup of immunologically cold TNBCs. I provide preliminary evidence of the relationship between germinal centre B cell responses in lymph nodes and tumours, which ultimately may influence an inferior disease trajectory for these high-risk TNBC patients.
| Date of Award | 1 Sept 2023 |
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| Original language | English |
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| Supervisor | Anita Grigoriadis (Supervisor) & Sophia Karagiannis (Supervisor) |