A chimeric antigen receptor uniquely recognizing MICA/B stress proteins provides an effective approach to target solid tumors.

Background: The advent of chimeric antigen receptor (CAR) T cell therapies has transformed the treatment of hematological malignancies; however, broader therapeutic success of CAR T cells has been limited in solid tumors because of their frequently heterogeneous composition. Stress proteins in the MICA and MICB (MICA/B) family are broadly expressed by tumor cells following DNA damage but are rapidly shed to evade immune detection.

Methods: We have developed a novel CAR targeting the conserved α3 domain of MICA/B (3MICA/B CAR) and incorporated it into a multiplexed-engineered induced pluripotent stem cell (iPSC)-derived natural killer (NK) cell (3MICA/B CAR iNK) that expressed a shedding-resistant form of the CD16 Fc receptor to enable tumor recognition through two major targeting receptors.

TREM2 macrophages drive NK cell paucity and dysfunction in lung cancer.

Natural killer (NK) cells are commonly reduced in human tumors, enabling many to evade surveillance. Here, we sought to identify cues that alter NK cell activity in tumors. We found that, in human lung cancer, the presence of NK cells inversely correlated with that of monocyte-derived macrophages (mo-macs).

The Latest Breakthroughs in Immunotherapy for Acute Myeloid Leukemia, with a Special Focus on NKG2D Ligands.

Acute myeloid leukemia (AML) is a hematological malignancy characterized by clonal expansion of stem and myeloid progenitor cells. Immunotherapy has revolutionized the care for other cancers such as solid tumors and lymphomas, and has the potential to effectively treat AML. There has been substantial progress in the developments of immunotherapeutic approaches for AML over the last several years, including the development of antibodies that further increase the innate immunogenicity of leukemia cells by the inhibition of NKG2D ligand-particularly MICA and MICB-shedding, chimeric proteins such as IL-15 superagonist that expand natural killer (NK) cells, blockers of immunologic checkpoints such as NKG2A, and chemicals that indirectly increase expression of immune stimulatory proteins in leukemia stem cells.

MICA/B antibody induces macrophage-mediated immunity against acute myeloid leukemia.

Acute myeloid leukemia (AML) is a clonal hematopoietic stem and progenitor cell malignancy characterized by poor clinical outcomes. Major histocompatibility complex class I polypeptide-related sequence A and B (MICA/B) are stress proteins expressed by cancer cells, and antibody-mediated inhibition of MICA/B shedding represents a novel approach to stimulate immunity against cancers. We found that the MICA/B antibody 7C6 potently inhibits the outgrowth of AML in 2 models in immunocompetent mice.

NK Cell Interaction With Platelets and Myeloid Cells in the Tumor Milieu.

Natural killer (NK) cells recognize and kill tumor cells germ-line encoded receptors and polarized degranulation of cytotoxic molecules, respectively. As such, NK cells help to inhibit the development of cancers. The activating receptor NKG2D induces NK cell-mediated killing of metastasizing tumor cells by recognition of the stress-induced ligands MICA, MICB, and ULBP1-6.

NKG2D and MICA/B shedding: a 'tag game' between NK cells and malignant cells.

Natural killer (NK) cells are innate lymphocytes with cytotoxic functions and recognise target cells with the NK group 2D (NKG2D) receptor. Tumor cells are marked for NK-cell-mediated destruction upon expression of MICA and MICB (MICA/B), which are NKG2D ligands upregulated by many human cancers in response to cellular stress pathways associated with malignant transformation such as DNA damage and accumulation of misfolded proteins. However, MICA/B proteins are downregulated by tumor cells via intriguing molecular mechanisms, such as post-translational modifications in which the external domains of MICA/B are proteolytically cleaved by surface proteases and shed into the extracellular space.

Inhibition of MICA and MICB Shedding Elicits NK-Cell-Mediated Immunity against Tumors Resistant to Cytotoxic T Cells.

Resistance to cytotoxic T cells is frequently mediated by loss of MHC class I expression or IFNγ signaling in tumor cells, such as mutations of or genes. Natural killer (NK) cells could potentially target such resistant tumors, but suitable NK-cell-based strategies remain to be developed. We hypothesized that such tumors could be targeted by NK cells if sufficient activating signals were provided.

Discovery of specialized NK cell populations infiltrating human melanoma metastases.

NK cells contribute to protective antitumor immunity, but little is known about the functional states of NK cells in human solid tumors. To address this issue, we performed single-cell RNA-seq analysis of NK cells isolated from human melanoma metastases, including lesions from patients who had progressed following checkpoint blockade. This analysis identified major differences in the transcriptional programs of tumor-infiltrating compared with circulating NK cells.

Visualization and quantification of NK cell-mediated cytotoxicity over extended time periods by image cytometry.

Natural killer (NK) cell-mediated cytotoxicity is traditionally measured using the chromium release assay, which measures the fraction of radioactive Cr released from dying target cells co-cultured with NK cells. However, the time frame of Cr release assays is limited to approximately 4 h due to spontaneous release of Cr. In the tumor microenvironment, interactions between NK cells and tumor cells occur over extended time periods, and NK cell-mediated cytotoxicity is modulated by cytokines produced by tumor cells and other immune cells.

Radiotherapy induces responses of lung cancer to CTLA-4 blockade.

Focal radiation therapy enhances systemic responses to anti-CTLA-4 antibodies in preclinical studies and in some patients with melanoma, but its efficacy in inducing systemic responses (abscopal responses) against tumors unresponsive to CTLA-4 blockade remained uncertain. Radiation therapy promotes the activation of anti-tumor T cells, an effect dependent on type I interferon induction in the irradiated tumor. The latter is essential for achieving abscopal responses in murine cancers.

Rapid CLIP dissociation from MHC II promotes an unusual antigen presentation pathway in autoimmunity.

A number of autoimmunity-associated MHC class II proteins interact only weakly with the invariant chain-derived class II-associated invariant chain peptide (CLIP). CLIP dissociates rapidly from I-A even in the absence of DM, and this property is related to the type 1 diabetes-associated β57 polymorphism. We generated knock-in non-obese diabetic (NOD) mice with a single amino acid change in the CLIP segment of the invariant chain in order to moderately slow CLIP dissociation from I-A These knock-in mice had a significantly reduced incidence of spontaneous type 1 diabetes and diminished islet infiltration by CD4 T cells, in particular T cells specific for fusion peptides generated by covalent linkage of proteolytic fragments within β cell secretory granules.

Antibody-mediated inhibition of MICA and MICB shedding promotes NK cell-driven tumor immunity.

MICA and MICB are expressed by many human cancers as a result of cellular stress, and can tag cells for elimination by cytotoxic lymphocytes through natural killer group 2D (NKG2D) receptor activation. However, tumors evade this immune recognition pathway through proteolytic shedding of MICA and MICB proteins. We rationally designed antibodies targeting the MICA α3 domain, the site of proteolytic shedding, and found that these antibodies prevented loss of cell surface MICA and MICB by human cancer cells.

A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing.

Many human cancers are resistant to immunotherapy, for reasons that are poorly understood. We used a genome-scale CRISPR-Cas9 screen to identify mechanisms of tumor cell resistance to killing by cytotoxic T cells, the central effectors of antitumor immunity. Inactivation of >100 genes-including , , and , which encode components of the PBAF form of the SWI/SNF chromatin remodeling complex-sensitized mouse B16F10 melanoma cells to killing by T cells.

Inhalation therapy with M1 inhibits experimental melanoma development and metastases in mice.

Background: M1 is a homeopathic medicine with immunostimulatory properties used mainly by cancer patients to complement current therapies. Metastatic melanoma is a skin-originated form of cancer without a single therapy able to produce high rate and sustained responses, which attracts the use of complementary therapies such as M1. However, M1's anti-melanoma effects remain to be pre-clinically demonstrated.

Suppression of Metastases Using a New Lymphocyte Checkpoint Target for Cancer Immunotherapy.

Unlabelled: CD96 has recently been shown as a negative regulator of mouse natural killer (NK)-cell activity, with Cd96(-/-)mice displaying hyperresponsive NK cells upon immune challenge. In this study, we have demonstrated that blocking CD96 with a monoclonal antibody inhibited experimental metastases in three different tumor models. The antimetastatic activity of anti-CD96 was dependent on NK cells, CD226 (DNAM-1), and IFNγ, but independent of activating Fc receptors.

Cytotoxic effect of inositol hexaphosphate and its Ni(II) complex on human acute leukemia Jurkat T cells.

Inositol hexaphosphate (InsP6) is present in cereals, legumes, nuts and seed oils and is biologically active against some tumor and cancer cells. Herein, this study aimed at evaluating the cellular toxicity, antiproliferative activity and effects on cell cycle progression of free InsP6 and InsP6-Ni(II) of leukemic T (Jurkat) and normal human cells. Treatments with InsP6 at concentrations between 1.

Natural Killer cell control of mutant melanoma during targeted therapy.

Pharmacologic inhibition of the mutant BRAF protein in advanced BRAF melanoma results in a high proportion of patients that respond, but few with durable responses. We have recently revealed that Natural Killer (NK) cells play an essential role in the inhibitor control of melanoma metastases in mice that may be therapeutically exploited to help overcome drug resistance.

Immunosurveillance and therapy of multiple myeloma are CD226 dependent.

Multiple myeloma (MM) is an age-dependent hematological malignancy. Evaluation of immune interactions that drive MM relies on in vitro experiments that do not reflect the complex cellular stroma involved in MM pathogenesis. Here we used Vk*MYC transgenic mice, which spontaneously develop MM, and demonstrated that the immune system plays a critical role in the control of MM progression and the response to treatment.

DNAM-1 expression marks an alternative program of NK cell maturation.

Natural killer (NK) cells comprise a heterogeneous population of cells important for pathogen defense and cancer surveillance. However, the functional significance of this diversity is not fully understood. Here, we demonstrate through transcriptional profiling and functional studies that the activating receptor DNAM-1 (CD226) identifies two distinct NK cell functional subsets: DNAM-1(+) and DNAM-1(-) NK cells.

Natural killer cells are essential for the ability of BRAF inhibitors to control BRAFV600E-mutant metastatic melanoma.

BRAF(V600E) is a major oncogenic mutation found in approximately 50% of human melanoma that confers constitutive activation of the MAPK pathway and increased melanoma growth. Inhibition of BRAF(V600E) by oncogene targeting therapy increases overall survival of patients with melanoma, but is unable to produce many durable responses. Adaptive drug resistance remains the main limitation to BRAF(V600E) inhibitor clinical efficacy and immune-based strategies could be useful to overcome disease relapse.

Cytotoxicity and apoptogenic effects of Lafoensia pacari.

Ethnopharmacological Relevance: The stem barks of Lafoensia pacari have been traditionally used not only by South Amerindians but also by Brazilian and Paraguayan populations for treating a variety of unhealthy conditions to which their biological potential has been scientifically documented in several reports over the last decade. Although its anticancer usage is also popular, no scientific support for such activity has been found.

Aim: To provide scientific evidence for the anticancer popularity of Lafoensia pacari.

DNAM-1 control of natural killer cells functions through nectin and nectin-like proteins.

Natural killer (NK) cells represent key innate immune cells that restrain viral infection and malignant transformation and help mount an adaptive immune response. To perform such complicated tasks, NK cells express a wide set of inhibitory and activating receptors that alert them against cellular stress without damaging healthy cells. A new family of receptors that recognize nectin and nectin-like molecules has recently emerged as a critical regulator of NK cell functions.