Abstract
Small Cell Lung Cancer (SCLC) accounts for 15-20% of all lung cancers andkills at least one person every 2 hours in the UK. There is no effective
treatment and overall 2-year survival is less than 5%. Patients with SCLC have
poorly understood local and systemic immune defects. Previous studies have
shown several important defects in cell-mediated immune responses in patients
with SCLC. A better understanding of interactions between SCLC tumour cells
and immune cells may lead to the development of novel therapeutic
approaches. There is increasing recognition that immunological biomarkers may
add to traditional histological analyses and can be exploited in the management
of multiple epithelial malignancies. There are currently no such markers used in
the management of SCLC.
In my PhD project, I have shown that cell lines from different SCLC patients
have differential immunosuppressive capabilities. These properties are
mediated by the secretion of differing levels of soluble molecules that can
suppress the mixed leukocyte reaction (MLR) and CD4+ T cell proliferation,
induce IL-10 secretion and differentiation of functional
CD4+CD25+CD127+FoxP3+Helios- regulatory T cells (Tregs) from naïve CD4+ T
cells. IL-15 is secreted by SCLC cells in culture in proportion to their
immunosuppressive capability. Its in vivo relevance is supported by its
presence in tumour biopsy samples. The suppressive effect on CD4+ T cell
proliferation and the induction of Treg cell population was not affected by
blocking IL-10 or TGF-β signalling but was partially reversed by blocking IL-15
activity. Therefore, IL-15 is one, though not the only, soluble molecule produced
by SCLC cells to mediate immune suppression by inducing increased
population of Treg cells. This may represent a mechanism by which SCLC cells
can suppress the immune response.
In addition, SCLC cells supressed TNF-α release from monocytes in response
to LPS stimulation, down-regulated expression of CD16 and CD86 and upregulated
expression of CD163 and CD206 on monocyte-derived macrophages
(MDMs) upon activation. This M2-like phenotype poralization was associated
with decreased TNF-α and IL-6 production and increased IL-10 secretion.
These effects were abrogated by blocking the signalling of bombesin-like
peptides (BLPs) that are neuropeptides produced by SCLC cells using a GRP
receptor (GRP-R) antagonist. Therefore, the polarization of macrophages to an
M2-like phenotype by SCLC cell-derived BLPs may represent another
mechanism by which SCLC tumours suppress the immune response.
Finally, SCLC tumour biopsies were shown to be infiltrated with various
mononuclear immune cells and Treg cells. CD45 and FoxP3 were used as paninflammatory
cell and Treg cell markers respectively. An elevated CD45+
infiltrate was predictive of prolonged survival in SCLC independent of age, sex,
stage or treatment strategy. An elevated FoxP3+/CD45+ ratio was predictive of a
significantly worse prognosis.
This study identifies potential mechanisms by which SCLC tumour cells may
downregulate local and systemic immune response, and also identifies an
independent prognostic marker to predict patient survival in SCLC. Further, IL-
15 and BLPs are potential novel therapeutic targets in SCLC.
| Date of Award | 2016 |
|---|---|
| Original language | English |
| Awarding Institution |
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| Supervisor | Tariq Sethi (Supervisor) & Frank McCaughan (Supervisor) |