Invariant NKT cells metabolically adapt to the acute myeloid leukaemia environment

Abstract

Acute myeloid leukaemia (AML) creates an immunosuppressive environment to conventional T cells through Arginase 2 (ARG2)-induced 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. Following in vitro cross-talk invariant natural killer T (iNKT) cells become activated, upregulate mitochondrial capacity, and release IFN-γ. iNKT retain their ability to proliferate and be activated despite the low arginine AML environment, due to the upregulation of Large Neutral Amino Acid Transporter-1 (LAT-1) and Argininosuccinate Synthetase 1 (ASS)-dependent amino acid pathways, resulting in AML cell death. T cell proliferation is restored in vitro and in vivo. The capacity of iNKT cells to restore antigen-specific T cell immunity was similarly demonstrated against myeloid-derived suppressor cells (MDSCs) in wild-type and Jα18−/− syngeneic lymphoma-bearing models in vivo. Thus, stimulation of iNKT cell activity has the potential as an immunotherapy against AML or as an adjunct to boost antigen-specific T cell immunotherapies in haematological or solid cancers.

Natural Killer T Cell Diversity and Immunotherapy

“…Importantly, this recovery of T cell activation was found both in vitro and in a syngeneic lymphoma-bearing model. In summary, this study highlights how iNKT cells adapt to the immunosuppressive AML environment, resulting in a direct reduction in cancer burden and the restoration of T cell function, suggesting that these cells could be potential targets for treatment in this type of cancer [192]. Regarding cancer progression, another aspect to consider is metastasis, where iNKT cells also play a pivotal role.…”

“…The latter leads to increased ARG2 expression and the viability of AML myeloblasts. The adaptation of iNKT cells in this context is driven by the overactivation of the large neutral amino acid transporter (LAT-1) and argininosuccinate synthase 1 (ASS) pathways [192]. In this study, co-cultures of AML cells from diagnosed patients were conducted in the presence of α-GalCer with iNKTs alone or with T cells obtained from healthy donors.…”

Dendritic Cells as a Therapeutic Strategy in Acute Myeloid Leukemia: Vaccines

“…Among the therapeutic possibilities in these circumstances is IT, where DCs enter the scene. They have been considered a promising therapeutic option since they have the ability to interact and activate CD8+ T lymphocytes, NK, and NKT cells, which are mainly responsible for the elimination of neoplastic cells or as an adjunct to boost antigen-specific T cell ITs in AML [ 5 , 70 , 71 , 72 ].…”

Beyond αβ T cells: NK, iNKT, and γδT cell biology in leukemic patients and potential for off-the-shelf adoptive cell therapies for AML

“…Stavrou et al. showed that ex vivo expanded human iNKT cells recognized and killed AML cells in a CD1d-TCR-dependent manner, and also helped restore anti-leukemic activity of T cells despite an immunosuppressive leukemic microenvironment ( 151 ). Other studies examined anti-leukemic activity, as well as effects of iNKT cells on GHVD simultaneously.…”