Constantinou, Georgia; (2024) Investigating immunity and cancer in a mouse model of PTEN hamartoma tumour syndrome (PHTS). Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

PTEN Hamartoma Tumour Syndrome (PHTS) is a rare human condition in which patients possess heterozygous germline defects in the PTEN tumour suppressor gene, resulting in disrupted PI3K signalling. PHTS predisposes to the development of specific solid tumours, macrocephaly and autism spectrum disorder, phenotypes which are mirrored in heterozygous Pten+/- mice. Emerging evidence shows that PHTS can also result in immune dysfunction. Using murine models, Pten gene knock-out approaches in specific leukocyte subpopulations has been extensively studied and has implicated PTEN in immune regulation, however, the immune impact of systemic heterozygous PTEN inactivation, as in PHTS, remains unknown. Here, using flow cytometry and ELISA techniques, I characterised the immune system of Pten+/- mice to elucidate how systemic heterozygous PTEN loss impacts the immune system to thus shedding light on the human condition. I also aimed to identify a role of impaired immunity in Pten+/- mice within tumourigenesis by utilising transplantable tumour models and bone marrow reconstitutions experiments to investigate whether the immune system could be a potential target to improve the tumour phenotypes in these mice. Finally, I tested, in vivo, the impact of two immunomodulatory drugs: RB50-LV29, a preclinical compound related to leniolisib, a PI3Kδ inhibitor approved for use in Activated PI3Kδ Syndrome (APDS) as well as rapamycin, an mTOR inhibitor that has been trialled in PHTS patients. Pten+/- mice showed lymphadenopathy and splenomegaly, with subtle but variable perturbations in the B cell compartment and mild alterations in the myeloid compartment at old age. More prominent changes were apparent in T cells, including an inverted CD4+/CD8+ ratio and increased proportions of FoxP3+Tregs, CD25- FoxP3+Tregs and CD8+ effector memory cells, indicative of a loss of Treg function. The immune alterations observed in Pten+/- mice occur as early as 6 weeks of age and fluctuate throughout the life span of the mouse. These immune phenotypes were mild, akin to those reported in PHTS patients and could be normalised by RB50-LV29 but to a lesser degree with rapamycin. While some immune responses remained intact in Pten+/- mice, for example an unaltered NP-specific antibody production upon immunisation with NP-KLH, they show evidence for reduced ability to control subcutaneously inoculated MC38 colon tumours. 6 months treatment with RB50-LV29 to Pten+/- mice reduced splenomegaly and lymphadenopathy, resulting in improved overall survival, but did not impact on the development of solid tumours, arguing against a key role of immune dysregulation in cancer development in Pten+/- mice. In addition to this evidence, lethally irradiated Pten+/+ mice reconstituted with Pten+/- bone marrow did not develop tumours, however, did largely present with immune defects comparable to those developed by non irradiated Pten+/- mice highlighting that many immune perturbations arise due to immune cell intrinsic effects. Taken together, these data uncover the potential of pharmacological PI3Kδ inhibition to ameliorate immune defects in PHTS and to exert anti-cancer activity on established tumours. However, such treatment is unlikely to be useful in prevention of solid tumour development in this syndrome, with long-term treatment likely to enhance tumour progression.

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