Innate production of T[H]2 cytokines by adipose tissue-associated c-Kit[+]Sca-1[+] lymphoid cells

Natural killer (NK) cells can swiftly kill multiple adjacent cells if these show surface markers associated with oncogenic transformation. This property, which is unique among immune cells, and their capacity to enhance antibody and T cell responses support a role for NK cells as anticancer agents. Although tumours may develop several mechanisms to resist attacks from endogenous NK cells, ex vivo activation, expansion and genetic modification of NK cells can greatly increase their antitumour activity and equip them to overcome resistance. Some of these methods have been translated into clinical-grade platforms and support clinical trials of NK cell infusions in patients with haematological malignancies or solid tumours, which have yielded encouraging results so far. The next generation of NK cell products will be engineered to enhance activating signals and proliferation, suppress inhibitory signals and promote their homing to tumours. These modifications promise to significantly increase their clinical activity. Finally, there is emerging evidence of increased NK cell-mediated tumour cell killing in the context of molecularly targeted therapies. These observations, in addition to the capacity of NK cells to magnify immune responses, suggest that NK cells are poised to become key components of multipronged therapeutic strategies for cancer. Natural killer (NK) cells have a primordial role in tumour immunosurveillance. Given their potent antitumour activity, therapeutic manipulation of NK cells provides an attractive strategy for cancer treatment. This Review discusses new approaches to activate NK cells, increase their proliferation in vivo and increase their capacity to recognize tumour cells.

NK cells for cancer immunotherapy.

Distinct Early Serological Signatures Track with SARS-CoV-2 Survival.

Through the successes of checkpoint blockade and adoptive cellular therapy, immunotherapy has become an established treatment modality for cancer. Cellular metabolism has emerged as a critical determinant of the viability and function of both cancer cells and immune cells. In order to sustain prodigious anabolic needs, tumours employ a specialized metabolism that differs from untransformed somatic cells. This metabolism leads to a tumour microenvironment that is commonly acidic, hypoxic and/or depleted of critical nutrients required by immune cells. In this context, tumour metabolism itself is a checkpoint that can limit immune-mediated tumour destruction. Because our understanding of immune cell metabolism and cancer metabolism has grown significantly in the past decade, we are on the cusp of being able to unravel the interaction of cancer cell metabolism and immune metabolism in therapeutically meaningful ways. Although there are metabolic processes that are seemingly fundamental to both cancer and responding immune cells, metabolic heterogeneity and plasticity may serve to distinguish the two. As such, understanding the differential metabolic requirements of the diverse cells that comprise an immune response to cancer offers an opportunity to selectively regulate immune cell function. Such a nuanced evaluation of cancer and immune metabolism can uncover metabolic vulnerabilities and therapeutic windows upon which to intervene for enhanced immunotherapy.

Metabolism of immune cells in cancer

Targeting the untargetable KRAS in cancer therapy.

Dysfunction of Natural Killer Cells by FBP1-Induced Inhibition of Glycolysis during Lung Cancer Progression

Natural killer (NK) cells are reported to have immunological memory, with CD49a+ liver-resident NK cells shown to confer hapten-specific memory responses, but how this memory is induced or maintained is unclear. Here we show that memory type I innate lymphoid cells (ILC1s), which express IL-7Rα, are generated in the lymph nodes (LNs) and require IL-7R signaling to maintain their longevity in the liver. Hapten sensitization initiates CXCR3-dependent recruitment of IL-7Rα+ ILC1s into skin-draining LNs, where they are primed and acquire hapten-specific memory potential. Memory IL-7Rα+ ILC1s then exit draining LNs and are preferentially recruited, via CXCR6, to reside in the liver. Moreover, long-term blockade of IL-7R signaling significantly reduces ILC1-mediated memory responses. Thus, our results identify a memory IL-7Rα+ ILC1 population and reveal a LN-liver axis that is essential for ILC1 memory generation and long-term maintenance. Natural killer cells may respond better on second antigen encounters, but how this memory is induced or maintained in vivo is not clear. Here the authors show that memory NK cells expressing interleukin-7 (IL-7) receptor are induced in the lymph nodes but later recruited to liver for long term, IL-7 dependent survival and memory maintenance.

/pdf/memory-formation-and-long-term-maintenance-of-il-7ra-ilc1s-4r84e89w5v.pdf

Memory formation and long-term maintenance of IL-7Rα+ ILC1s via a lymph node-liver axis.

The lungs, a special site that is frequently challenged by tumors, pathogens and other environmental insults, are populated by large numbers of innate immune cells. Among these, natural killer (NK) cells are gaining increasing attention. Recent studies have revealed that NK cells are heterogeneous populations consisting of distinct subpopulations with diverse characteristics, some of which are determined by their local tissue microenvironment. Most current information about NK cells comes from studies of NK cells from the peripheral blood of humans and NK cells from the spleen and bone marrow of mice. However, the functions and phenotypes of lung NK cells differ from those of NK cells in other tissues. Here, we provide an overview of human and mouse lung NK cells in the context of homeostasis, pathogenic infections, asthma, chronic obstructive pulmonary disease (COPD) and lung cancer, mainly focusing on their phenotype, function, frequency, and their potential role in pathogenesis or immune defense. A comprehensive understanding of the biology of NK cells in the lungs will aid the development of NK cell-based immunotherapies for the treatment of lung diseases.

Natural Killer Cells in the Lungs.

Gemcitabine has been used as first-line chemotherapy against lung cancer, but many patients experience cancer recurrence. Activation of anti-tumor immunity in vivo has become an important way to prevent recurrence. Anti-tumor immune responses are often dependent upon the immunogenicity of tumors. In our study, we observed that low-dose gemcitabine treatment enhanced the immunogenicity of lung cancer by increasing the exposure of calreticulin, high mobility group box 1, and upregulating expression of NKG2D ligands. Further studies demonstrated that low-dose gemcitabine treatment increased interferon-γ expression and NK-cell activation in mice. Low-dose gemcitabine treatment was sufficient for inhibiting tumor growth with few side effects in vivo. These data suggest that low-dose gemcitabine-induced immunochemotherapy activated antitumor immunity in immunocompetent patients.

/pdf/low-dose-gemcitabine-treatment-enhances-immunogenicity-and-4e1qtb6gw0.pdf

Low-Dose Gemcitabine Treatment Enhances Immunogenicity and Natural Killer Cell-Driven Tumor Immunity in Lung Cancer

Natural killer (NK) cells are the host's first line of defense against tumors and viral infections without prior sensitization. It is increasingly accepted that NK cells belong to the innate lymphoid cell (ILC) family. Other ILCs, comprising ILC1s, ILC2s, ILC3s and lymphoid tissue inducer (LTi) cells, are largely non-cytotoxic, tissue-resident cells, which function to protect local microenvironments against tissue insults and maintain homeostasis. Recently, evidence has accumulated that metabolism supports many aspects of the biology of NK cells and other ILCs, and that metabolic reprogramming regulates their development and function. Here, we outline the current understanding of ILC metabolism, and describe how metabolic processes are affected, and how metabolic defects are coupled to dysfunction of ILCs, in disease settings. Furthermore, we summarize the current and potential directions for immunotherapy involving targeting of ILC metabolism. Finally, we discuss the open questions in the rapidly expanding field of ILC metabolism.

/pdf/metabolism-of-natural-killer-cells-and-other-innate-lymphoid-4rbu1uakdy.pdf

Jingjing Cong

Papers

Dysfunction of Natural Killer Cells by FBP1-Induced Inhibition of Glycolysis during Lung Cancer Progression

Memory formation and long-term maintenance of IL-7Rα+ ILC1s via a lymph node-liver axis.

Natural Killer Cells in the Lungs.

Low-Dose Gemcitabine Treatment Enhances Immunogenicity and Natural Killer Cell-Driven Tumor Immunity in Lung Cancer

Metabolism of Natural Killer Cells and Other Innate Lymphoid Cells.