Abstract: SAT 214

The Interplay Between Immune Cell Function and Thyroid Cancer Development in Patients with Cowden Syndrome

Presenter:


Abstract


Introduction: We have previously shown that activation of PI3K/Akt/mTOR signaling results in a shift towards aerobic glycolysis, providing energy for innate immune cell activation and the reprogramming of tumor associated macrophages in thyroid carcinoma (TC) (1). Cowden syndrome (CS) is a hereditary cancer syndrome caused by germline mutations in PTEN with subsequent activation of the PI3K/Akt/mTOR signaling. Carriers of PTEN mutations are at high risk to develop various malignant tumors including TC (2). view more

Introduction: We have previously shown that activation of PI3K/Akt/mTOR signaling results in a shift towards aerobic glycolysis, providing energy for innate immune cell activation and the reprogramming of tumor associated macrophages in thyroid carcinoma (TC) (1). Cowden syndrome (CS) is a hereditary cancer syndrome caused by germline mutations in PTEN with subsequent activation of the PI3K/Akt/mTOR signaling. Carriers of PTEN mutations are at high risk to develop various malignant tumors including TC (2). We hypothesize that inactivating germline PTEN mutations in immune cells of CS patients have carcinogenic effects either through breaches in antitumoral immunity or dysregulated inflammation in the tumor microenvironment.

Aim: To assess the effect of germline PTEN mutation on the function of innate immune cells and its relation with TC development in patients with CS.

Methods: To study the effect of PTEN mutations on innate immune cell function, we performed ex-vivo peripheral blood mononuclear cells (PBMC) stimulation experiments in CS patients and healthy controls to assess cytokine production capacity upon stimulation with Toll-Like receptor, C-type lectin receptor and NOD-like receptor ligands. To study the interaction between PTEN mutated macrophages and TC, a co-culture model of TC cells/monocytes was used.

Results: The PBMC’s from CS patients showed 1.4 to 1.6-fold increased production of pro-inflammatory cytokines IL-6, TNFα and IL-1β, especially in response to Candida albicans (C-type lectin receptor ligand) stimulation (n=15, p<0.05). Furthermore, production of the anti-inflammatory cytokine IL-10 was also increased in CS patients (P<0.05). The PBMC’s lactate production, was significantly increased (n=10, p<0.05) in CS patients, indicating an increased rate of aerobic glycolysis as a result of increased PI3k/Akt/mTOR activation. Co-culture of human monocytes with TC cell-lines TPC-1 (RET/PTC rearrangement) and FTC-133 (PTEN inactivation) induces an increased production of pro-inflammatory cytokines (IL-6 and TNFα) (n=10; P<0.05). Moreover, co-culture of monocytes from CS patients with TC cell lines resulted in differentiation of macrophages showing a significantly higher pro-inflammatory cytokine production compared to macrophages differentiated from healthy controls.

Conclusion: Innate immune cells from CS patients show a hyperinflammatory cytokine profile compared with control individuals. This effect is most likely due to an increased capacity of cells from CS patients to mount glycolysis, known to stimulate inflammation. Furthermore, co-incubation of monocytes from CS patients with TC cells accentuated proinflammatory cytokine production. We thus hypothesize that the dysregulated inflammatory profile in CS patients contributes to cancer development in these patients.

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