Intratumoral natural killer cells show reduced effector and cytolytic properties and control the differentiation of effector Th1 cells

Abstract

Natural killer (NK) cells are known to have effector and cytolytic properties to kill virus infected or tumor cells spontaneously. Due to these properties, NK cells have been used as an adoptive cellular therapy to control tumor growth in various clinical trials but have shown limited clinical benefits. This indicates that our knowledge about phenotypic and functional differences in NK cells within the tumor microenvironment and secondary lymphoid tissues is incomplete. In this work, we report that B16F10 cellinduced melanoma recruits the CD11b C CD27C subset of NK cells at a very early stage during tumor progression. These intratumoral NK cells showed increased expression of CD69, reduced inhibitory receptor KLRG1, and decreased proliferative ability. As compared to splenic NK cells, intratumoral NK cells showed decreased expression of activating receptors NKG2D, Ly49D and Ly49H; increased inhibitory receptors, NKG2A and Ly49A; decreased cytokines IFNg and GM-CSF; decreased cytokine receptors IL-21R, IL-6Ra, and CD122 expression. Depletion of NK cells led to decrease peripheral as well as intratumoral effector CD4 C T-bet C cells (Th1), and increased tumor growth. Furthermore, purified NK cells showed increased differentiation of Th1 cells in an IFNg-dependent manner. Anti-NKG2D in the culture promoted differentiation of effector Th1 cells. Collectively, these observations suggest that intratumoral NK cells possess several inhibitory functions that can be partly reversed by signaling through the NKG2D receptor or by cytokine stimulation, which then leads to increased differentiation of effector Th1 cells.

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

“…Exhausted NK cells share some phenotypes with exhausted CD8 + T-cells, namely downregulation of effector cytokines such as IFN-γ, impaired degranulation and cytotoxicity, downregulation of activating receptors such as NKG2D, upregulation of inhibitory receptors such as NKG2A, and transcriptional changes that promote exhaustion, i.e., downregulation of transcription factors including Eomesodermin and T-bet (20,(81)(82)(83)(84)(85)(86). Recent studies further characterized inhibitory checkpoint receptors that promote NK cell dysfunction during malignancy.…”

Trial watch: Immunogenic cell death induction by anticancer chemotherapeutics

“…136,147,150,151 Additional details about ICD-associated signaling pathways and resistance mechanisms can be found in various publications from us and others. [2][3][4]7,40,[152][153][154][155] Of note, only a limited number of cell death inducers can elicit bona fide ICD, and this capacity cannot be predicted on the basis of structural or functional similarities.…”

The Interplay Between Innate Lymphoid Cells and the Tumor Microenvironment

“…ILCs may also directly modulate the quality of T cell responses without prior DC crosstalk. NK cell-secreted IFNγ, for example, was shown to promote Th1 polarization in the lymph nodes in mouse models of infection (131,132). A close cooperation between NK cells and T cells has also been shown in established lung carcinoma, where the stimulation of NK cells induced the recruitment of highly active T cells, leading to a more efficient tumor control (133).…”