Abstract Natural killer (NK) cells, a subgroup of innate lymphoid cells, act as the first line of defense against cancer. Although some evidence shows that NK cells can develop in secondary lymphoid tissues, NK cells develop mainly in the bone marrow (BM) and egress into the blood circulation when they mature. They then migrate to and settle down in peripheral tissues, though some special subsets home back into the BM or secondary lymphoid organs. Owing to its success in allogeneic adoptive transfer for cancer treatment and its “off-the-shelf” potential, NK cell-based immunotherapy is attracting increasing attention in the treatment of various cancers. However, insufficient infiltration of adoptively transferred NK cells limits clinical utility, especially for solid tumors. Expansion of NK cells or engineered chimeric antigen receptor (CAR) NK cells ex vivo prior to adoptive transfer by using various cytokines alters the profiles of chemokine receptors, which affects the infiltration of transferred NK cells into tumor tissue. Several factors control NK cell trafficking and homing, including cell-intrinsic factors (e.g., transcriptional factors), cell-extrinsic factors (e.g., integrins, selectins, chemokines and their corresponding receptors, signals induced by cytokines, sphingosine-1-phosphate (S1P), etc.), and the cellular microenvironment. Here, we summarize the profiles and mechanisms of NK cell homing and trafficking at steady state and during tumor development, aiming to improve NK cell-based cancer immunotherapy. 

/pdf/natural-killer-cell-homing-and-trafficking-in-tissues-and-2wl2db56.pdf

Natural killer cell homing and trafficking in tissues and tumors: from biology to application

Harnessing IL-15 signaling to potentiate NK cell-mediated cancer immunotherapy.

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) dysregulates antiviral signaling, immune response, and cell metabolism in human body. Viral genome and proteins hijack host metabolic network to support viral biogenesis and propagation. However, the regulatory mechanism of SARS‐CoV‐2‐induced metabolic dysfunction has not been elucidated until recently. Multiomic studies of coronavirus disease 2019 (COVID‐19) revealed an intensive interaction between host metabolic regulators and viral proteins. SARS‐CoV‐2 deregulated cellular metabolism in blood, intestine, liver, pancreas, fat, and immune cells. Host metabolism supported almost every stage of viral lifecycle. Strikingly, viral proteins were found to interact with metabolic enzymes in different cellular compartments. Biochemical and genetic assays also identified key regulatory nodes and metabolic dependencies of viral replication. Of note, cholesterol metabolism, lipid metabolism, and glucose metabolism are broadly involved in viral lifecycle. Here, we summarized the current understanding of the hallmarks of COVID‐19 metabolism. SARS‐CoV‐2 infection remodels host cell metabolism, which in turn modulates viral biogenesis and replication. Remodeling of host metabolism creates metabolic vulnerability of SARS‐CoV‐2 replication, which could be explored to uncover new therapeutic targets. The efficacy of metabolic inhibitors against COVID‐19 is under investigation in several clinical trials. Ultimately, the knowledge of SARS‐CoV‐2‐induced metabolic reprogramming would accelerate drug repurposing or screening to combat the COVID‐19 pandemic.

COVID‐19 metabolism: Mechanisms and therapeutic targets

Abstract Having a hypoxic microenvironment is a common and salient feature of most solid tumors. Hypoxia has a profound effect on the biological behavior and malignant phenotype of cancer cells, mediates the effects of cancer chemotherapy, radiotherapy, and immunotherapy through complex mechanisms, and is closely associated with poor prognosis in various cancer patients. Accumulating studies have demonstrated that through normalization of the tumor vasculature, nanoparticle carriers and biocarriers can effectively increase the oxygen concentration in the tumor microenvironment, improve drug delivery and the efficacy of radiotherapy. They also increase infiltration of innate and adaptive anti-tumor immune cells to enhance the efficacy of immunotherapy. Furthermore, drugs targeting key genes associated with hypoxia, including hypoxia tracers, hypoxia-activated prodrugs, and drugs targeting hypoxia-inducible factors and downstream targets, can be used for visualization and quantitative analysis of tumor hypoxia and antitumor activity. However, the relationship between hypoxia and cancer is an area of research that requires further exploration. Here, we investigated the potential factors in the development of hypoxia in cancer, changes in signaling pathways that occur in cancer cells to adapt to hypoxic environments, the mechanisms of hypoxia-induced cancer immune tolerance, chemotherapeutic tolerance, and enhanced radiation tolerance, as well as the insights and applications of hypoxia in cancer therapy. 

/pdf/hypoxic-microenvironment-in-cancer-molecular-mechanisms-and-2xbbj46h.pdf

Hypoxic microenvironment in cancer: molecular mechanisms and therapeutic interventions

Reimagining antibody-dependent cellular cytotoxicity in cancer: the potential of natural killer cell engagers

Type I innate lymphoid cells (ILC1s) are critical regulators of inflammation and immunity in mammalian tissues. However, their function in cancer is mostly undefined. Here, we show that a high density of ILC1s induces leukemia stem cell (LSC) apoptosis in mice. At a lower density, ILC1s prevent LSCs from differentiating into leukemia progenitors and promote their differentiation into non-leukemic cells, thus blocking the production of terminal myeloid blasts. All of these effects, which require ILC1s to produce interferon-γ after cell-cell contact with LSCs, converge to suppress leukemogenesis in vivo. Conversely, the antileukemia potential of ILC1s wanes when JAK-STAT or PI3K-AKT signaling is inhibited. The relevant antileukemic properties of ILC1s are also functional in healthy individuals and impaired in individuals with acute myeloid leukemia (AML). Collectively, these findings identify ILC1s as anticancer immune cells that might be suitable for AML immunotherapy and provide a potential strategy to treat AML and prevent relapse of the disease. 

ILC1s Control Leukemia Stem Cell Fate and Limit Development of AML

Engineered natural killer (NK) cells represent a promising option for immune therapy option due to their immediate availability in allogeneic settings. Severe acute diseases, such as COVID-19, require targeted and immediate intervention. Here we show engineering of NK cells to express (1) soluble interleukin-15 (sIL15) for enhancing their survival and (2) a chimeric antigen receptor (CAR) consisting of an extracellular domain of ACE2, targeting the spike protein of SARS-CoV-2. These CAR NK cells (mACE2-CAR_sIL15 NK cells) bind to VSV-SARS-CoV-2 chimeric viral particles as well as the recombinant SARS-CoV-2 spike protein subunit S1 leading to enhanced NK cell production of TNF-α and IFN-γ and increased in vitro and in vivo cytotoxicity against cells expressing the spike protein. Administration of mACE2-CAR_sIL15 NK cells maintains body weight, reduces viral load, and prolongs survival of transgenic mice expressing human ACE2 upon infection with live SARS-CoV-2. These experiments, and the capacity of mACE2-CAR_sIL15 NK cells to retain their activity following cryopreservation, demonstrate their potential as an allogeneic off-the-shelf therapy for COVID-19 patients who are faced with limited treatment options. 

/pdf/off-the-shelf-car-natural-killer-cells-secreting-il-15-30vx6n3p.pdf

Off-the-shelf CAR natural killer cells secreting IL-15 target spike in treating COVID-19

Chemokines such as C-C motif ligand 5 (CCL5) regulate immune cell trafficking in the tumor microenvironment (TME) and govern tumor development, making them promising targets for cancer therapy. However, short half-lives and toxic off-target effects limit their application. Oncolytic viruses (OVs) have become attractive therapeutic agents. Here, we generate an oncolytic herpes simplex virus type 1 (oHSV) expressing a secretable single-chain variable fragment of the epidermal growth factor receptor (EGFR) antibody cetuximab linked to CCL5 by an Fc knob-into-hole strategy that produces heterodimers (OV-Cmab-CCL5). OV-Cmab-CCL5 permits continuous production of CCL5 in the TME, as it is redirected to EGFR+ glioblastoma (GBM) tumor cells. OV-Cmab-CCL5 infection of GBM significantly enhances the migration and activation of natural killer cells, macrophages and T cells; inhibits tumor EGFR signaling; reduces tumor size; and prolongs survival of GBM-bearing mice. Collectively, our data demonstrate that OV-Cmab-CCL5 offers a promising approach to improve OV therapy for solid tumors. 

Specific targeting of glioblastoma with an oncolytic virus expressing a cetuximab-CCL5 fusion protein via innate and adaptive immunity

T-cell lymphomas are aggressive lymphomas that often resist current therapy options or present with relapsed disease, making the development of more effective treatment regimens clinically important. Previously, we have shown that CD4 CAR can effectively target T-cell malignancies in preclinical studies. As IL-15 has been shown to strengthen the anti-tumor response, we have modified CD4 CAR to secrete an IL-15/IL-15sushi complex. These CD4-IL15/IL15sushi CAR T cells and NK92 cells efficiently eliminated CD4+ leukemic cell lines in co-culture assays. Additionally, CD4-IL15/IL15sushi CAR out-performed CD4 CAR in in vivo models, demonstrating a benefit to IL-15/IL-15sushi inclusion. In a Phase I clinical trial, CD4-IL15/IL15sushi CAR T cells were tested for safety in three patients with different T-cell lymphomas. Infusion of CD4-IL15/IL15sushi CAR T cells was well-tolerated by the patients without significant adverse effects and led to the remission of their lymphomas. Additionally, infusion led to the depletion of CD4+ Treg cells and expansion of CD3+CD8+ T cells and NK cells. These results suggest that CD4-IL15/IL15sushi CAR T cells may be a safe and effective treatment for patients with relapsed or refractory T-cell lymphomas, where new treatment options are needed.

/pdf/treatment-of-aggressive-t-cell-lymphoma-leukemia-with-anti-30kfyxd7.pdf

L. Tian

Papers

Natural killer cell homing and trafficking in tissues and tumors: from biology to application

ILC1s Control Leukemia Stem Cell Fate and Limit Development of AML

Off-the-shelf CAR natural killer cells secreting IL-15 target spike in treating COVID-19

Specific targeting of glioblastoma with an oncolytic virus expressing a cetuximab-CCL5 fusion protein via innate and adaptive immunity

Treatment of aggressive T-cell lymphoma/leukemia with anti-CD4 CAR T cells