IL-21-mediated reversal of NK cell exhaustion facilitates anti-tumour immunity in MHC class I-deficient tumours

Abstract

During cancer immunoediting, loss of major histocompatibility complex class I (MHC-I) in neoplasm contributes to the evasion of tumours from host immune system. Recent studies have demonstrated that most natural killer (NK) cells that are found in advanced cancers are defective, releasing the malignant MHC-I-deficient tumours from NK-cell-dependent immune control. Here, we show that a natural killer T (NKT)-cell-ligand-loaded tumour-antigen expressing antigen-presenting cell (APC)-based vaccine effectively eradicates these advanced tumours. During this process, we find that the co-expression of Tim-3 and PD-1 marks functionally exhausted NK cells in advanced tumours and that MHC-I downregulation in tumours is closely associated with the induction of NK-cell exhaustion in both tumour-bearing mice and cancer patients. Furthermore, the recovery of NK-cell function by IL-21 is critical for the anti-tumour effects of the vaccine against advanced tumours. These results reveal the process involved in the induction of NK-cell dysfunction in advanced cancers and provide a guidance for the development of strategies for cancer immunotherapy.

Directed Differentiation of Mobilized Hematopoietic Stem and Progenitor Cells into Functional NK Cells with Enhanced Antitumor Activity

“…Importantly, as seen for the extent of differentiation of NK cells from poor responders, PB-CD34 + cells of two donors that gave rise to NK cells without measurable cytotoxicity if generated only with cytokines yielded NK cells that efficiently killed K562 cells when stimulated with K562/41BBL/mb15/mb21 cells during differentiation and expansion. This differential activity of NK cells derived from the same donor HSCs may be attributed to the previously described ability of IL-21 to reverse exhaustion and restore antitumor activity of NK cells after long-term culture [14,53]. Furthermore, in addition to killing of K562 cells, we observed enhanced lysis of target cells of different solid tumor origins by NK cells generated with the help of K562/41BBL/mb15/mb21 feeder cells.…”

Targeting tumors with IL-21 reshapes the tumor microenvironment by proliferating PD-1intTim-3–CD8+ T cells

“…IL-21 resulted in a lower level of PD-1 on tumor antigen-specific CD8 + T cells. IL-21 was reported to reverse the innate NK cell dysfunction in tumors (56). We wondered whether IL-21 could also affect the adaptive dysfunctional CD8 + T cells and tested antigen-specific T cell responses after IL-21 treatment using MC38-OVA.…”

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

“…Here, as well, blocking TIM-3 with antibodies increased NK cell cytotoxicity and cytokine secretion. Additional recent studies identified TIM-3 expression as a marker of NK cell dysfunction and disease severity in colorectal cancer, esophageal cancer, endometrial cancer, and bladder cancer (96,(98)(99)(100)(101). Interestingly, TIM-3 engagement was initially shown to increase the expression of IFN-γ by NK cells in response to galectin-9, the β-galactoside binding lectin (123).…”