Investigating the immunosuppressive microenvironment created by acute myeloid leukaemia using invariant natural killer T cells as a novel therapeutic approach

Stavrou, Victoria (2022). Investigating the immunosuppressive microenvironment created by acute myeloid leukaemia using invariant natural killer T cells as a novel therapeutic approach. University of Birmingham. Ph.D.

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Abstract

Acute myeloid leukaemia (AML) creates an immunosuppressive microenvironment to conventional T cells through Arginase 2 (ARG2) inducing arginine depletion. We identify that AML blasts release the acute phase protein serum amyloid A (SAA), which acts in an autocrine manner to upregulate ARG2 expression and activity and promote AML blast viability.

Invariant natural killer T cells (iNKT) are a distinct population of T-cells with the unique ability to bridge the innate and adaptive immune system by mediating a range of immune responses and play a key role in tumour immunosurveillance. In AML the low level of iNKT cells post stem cell transplant is associated with poor overall survival; however it is unclear if iNKT cells directly regulate the growth of malignant cells. We establish that iNKT cells can detect and interact with AML blasts in a CD1d/CD40 dependent manner. α-GalCer-loaded AML blasts induce potent iNKT cell activation resulting in release IFN-γ and initiating clonal expansion in vivo and in vitro. Activated iNKT cells can reduce tumour burden by directly killing AML blasts via granzyme B pathway inducing apoptosis.

Despite the low arginine AML microenvironment which is hostile to T cells, iNKT cells retain their ability to proliferate, become activated and elicit a cytotoxic response against AML due to the upregulation of LAT-1 and ASS-1 dependent amino acid pathways. Finally, activated iNKT cells can further restore T cell proliferation both in vitro and in vivo.

This illustrates that iNKT cells are key players in creating an anti-leukemic response, thus, stimulation of iNKT cell activity has the potential to be exploited as an immunotherapeutic approach against AML or as an adjunct to boost antigen-specific T cell immunotherapies in cancers.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):