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Impact of anti-CTLA4 and anti-PD1 on the cross talk between cancer and immune cells, underlying CAT-VTE
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Resumo(s)
Cancer-associated thrombosis (CAT) and venous thromboembolism (VTE) are frequent cancerrelated complications associated with high mortality, thus the identification of predictive markers urges.
Immune checkpoints inhibitors (ICI) used in cancer immunotherapy allow T cell activation against
cancer cells. Recent retrospective studies showed increased VTE following ICI administration in some
patients. Non-small cell lung cancer (NSCLC) is at high risk of thrombosis and the adoption of
immunotherapy as a first line treatment seems to be associated with coagulation-fibrinolysis
derangement. In melanoma, a very high-risk of thrombosis disease, few studies have addressed
increased risk of coagulation alterations associated to ICI.
For this project, we hypothesized that the action of ICI (anti-CTLA4 and anti-PD1) on immune
and cancer cells as well as on their interaction, accounts for an increased risk of CAT-VTE. Our goal is
to analyze this molecular crosstalk to identify possible prothrombotic biomarkers.
We pharmacologically modulated NSCLC and melanoma cell lines in co-culture with CD8+ T
cells (T CD8+
) and Myeloid-Derived Suppressor Cells (MDSC), isolated from healthy blood donors.
Immunofluorescence and flow cytometry analyses showed that T CD8+
and ICI increase cancer cell
death. The in vitro clotting assay showed that T CD8+
and ICI induce platelet aggregation dependent on
the relative quantity of T CD8+
. The Enzyme-Linked Immunosorbent Assay (ELISA) proposed that T
CD8+
and ICI differently disrupt Tissue Factor and Podoplanin levels, which were not restored by
MDSC exposure. The metabolic remodeling assessment by Nuclear Magnetic Resonance (NMR)
suggested differential concentrations of extracellular metabolites upon exposure to T CD8+
and ICI.
This study provides some insights about the interplay of immune cells, ICI and cancer cells,
influencing the coagulation status. The results obtained constitute a starting point on this theme, denoting
the need of further investigation underlying this dynamic, and opening important cues to follow towards
the definition of biomarkers.
Descrição
Tese de mestrado, Biologia Humana e Ambiente , 2023, Universidade de Lisboa, Faculdade de Ciências
Palavras-chave
Trombose associada a cancro (CAT) tromboembolismo venoso (VTE) Inibidores de checkpoint imunitários (ICI) Cancro de pulmão de não pequenas células (NSCLC) Melanoma Teses de mestrado - 2023