Hypoxia-inducible factor-1 alpha expression is induced by IL-2 via the PI3K/mTOR pathway in hypoxic NK cells and supports effector functions in NKL cells and ex vivo expanded NK cells.

Natural killer (NK) cells are cytotoxic innate lymphocytes that are specialized to kill tumor cells. NK cells are responsive to the primary cytokine IL-2 in the tumor microenvironment (TME), to activate its effector functions against tumors. Despite their inherent ability to kill tumor cells, dysfunctional NK cells observed within advanced solid tumors are associated with poor patient survival. Hypoxia in the TME is a major contributor to immune evasion in solid tumors that could contribute to impaired NK cell function. HIF-1α is a nodal regulator of hypoxia in driving the adaptive cellular responses to changes in oxygen concentrations. Whether HIF-1α is expressed in hypoxic NK cells in the context of IL-2 and whether its expression regulates NK cell effector function are unclear. Here, we report that freshly isolated NK cells from human peripheral blood in hypoxia could not stabilize HIF-1α protein coincident with impaired anti-tumor cytotoxicity. However, ex vivo expansion of these cells restored HIF-1α levels in hypoxia to promote antitumor cytotoxic functions. Similarly, the human NK cell line NKL expressed HIF-1α upon IL-2 stimulation in hypoxia and exhibited improved anti-tumor cytotoxicity and IFN-γ secretion. We found that ex vivo expanded human NK cells and NKL cells required the concerted activation of PI3K/mTOR pathway initiated by IL-2 signaling in combination with hypoxia for HIF-1α stabilization. These findings highlight that HIF-1α stabilization in hypoxia maximizes NK cell effector function and raises the prospect of NK cells as ideal therapeutic candidates for solid tumors.

Differential expression of nuclear hormone receptors by dendritic cell subsets in human vaginal mucosa and skin.

Nuclear hormone receptors (NHRs) expressed by dendritic cells (DCs), the major immune inducers and regulators, could play important roles in host immunity. Assessment of NHRs expressed by DCs in the vaginal mucosa (VM), in comparison with those expressed by DCs in other tissues, will thus help us understand the immunology of human vagina. This study identified 16 NHR transcripts that are differentially expressed among 8 different antigen-presenting cell (APC) subsets isolated from human VM, skin, and blood. The expression profiles of NHRs were largely tissue specific. VM APCs expressed increased levels of LXRA, RXRA, ESRRA, ESRRAP2, and PPARG, whereas skin and blood APCs expressed increased levels of NURR1, NOR1 and RARA. Of interest, female sex hormone receptors, ESR1 and PGR, were found to be mainly expressed by non-APC cell types in the VM; ESR1 by HLA-DR+CD34+ and PGR by HLA-DR- cells. ERα and PR were expressed by vimentin+ cells in the VM, but not in human skin. ERα, but not PR, was also expressed in CD10+ cells in the lamina propria of VM. In conclusion, NHR expression by APC subsets is tissue- and cell type-specific. Future studies on the roles of individual NHRs expressed by different cell types, including DC subsets, in the human VM are warranted.