Intratumoural administration of an NKT cell agonist with CpG promotes NKT cell infiltration associated with an enhanced antitumour response and abscopal effect.

Intratumoural administration of unmethylated cytosine-phosphate-guanine motifs (CpG) to stimulate toll-like receptor (TLR)-9 has been shown to induce tumour regression in preclinical studies and some efficacy in the clinic. Because activated natural killer T (NKT) cells can cooperate with pattern-recognition via TLRs to improve adaptive immune responses, we assessed the impact of combining a repeated dosing regimen of intratumoural CpG with a single intratumoural dose of the NKT cell agonist α-galactosylceramide (α-GalCer). The combination was superior to CpG alone at inducing regression of established tumours in several murine tumour models, primarily mediated by CD8 T cells.

Increased lipid metabolism impairs NK cell function and mediates adaptation to the lymphoma environment.

Natural killer (NK) cells play critical roles in protection against hematological malignancies but can acquire a dysfunctional state, which limits antitumor immunity. However, the underlying reasons for this impaired NK cell function remain to be uncovered. We found that NK cells in aggressive B-cell lymphoma underwent substantial transcriptional reprogramming associated with increased lipid metabolism, including elevated expression of the transcriptional regulator peroxisome activator receptor-γ (PPAR-γ).

NKT Cell-Driven Enhancement of Antitumor Immunity Induced by Clec9a-Targeted Tailorable Nanoemulsion.

Invariant natural killer T (iNKT) cells are a subset of lymphocytes with immune regulatory activity. Their ability to bridge the innate and adaptive immune systems has been studied using the glycolipid ligand α-galactosylceramide (αGC). To better harness the immune adjuvant properties of iNKT cells to enhance priming of antigen-specific CD8 T cells, we encapsulated both αGC and antigen in a Clec9a-targeted nanoemulsion (TNE) to deliver these molecules to cross-presenting CD8 dendritic cells (DC).

Interaction of neurotransmitters and neurochemicals with lymphocytes.

Neurotransmitters and neurochemicals can act on lymphocytes by binding to receptors expressed by lymphocytes. This review describes lymphocyte expression of receptors for a selection of neurotransmitters and neurochemicals, the anatomical locations where lymphocytes can interact with neurotransmitters, and the effects of the neurotransmitters on lymphocyte function. Implications for health and disease are also discussed.

Recruitment of Antigen Presenting Cells to Skin Draining Lymph Node From HPV16E7-Expressing Skin Requires E7-Rb Interaction.

"High-risk" human papillomaviruses (HPV) infect keratinocytes of squamous epithelia. The HPV16E7 protein induces epithelial hyperplasia by binding Rb family proteins and disrupting cell cycle termination. Murine skin expressing HPV16E7 as a transgene from a keratin 14 promoter (K14.

The prognostic significance of circulating tumor cells in head and neck and non-small-cell lung cancer.

Tumor biopsy is the gold standard for the assessment of clinical biomarkers for treatment. However, tumors change dynamically in response to therapy, and there remains a need for a more representative biomarker that can be assayed over the course of treatment. Circulating tumor cells (CTCs) may provide clinically important and comprehensive tumoral information that is predictive of treatment response and outcome.

Therapeutic vaccination with 4-1BB co-stimulation eradicates mouse acute myeloid leukemia.

Immunomodulatory therapies can effectively control haematological malignancies. Previously we reported the effectiveness of combination immunotherapies that centre on 4-1BB-targeted co-stimulation of CD8 + T cells, particularly when simultaneously harnessing the immune adjuvant properties of Natural Killer T (NKT) cells. The objective of this study was to assess the effectiveness of agonistic anti-4-1BB antibody-based combination therapy against two aggressive forms of acute myeloid leukemia (AML).

B cell lymphoma progression promotes the accumulation of circulating Ly6Clo monocytes with immunosuppressive activity.

Monocytosis is considered a poor prognostic factor for many cancers, including B cell lymphomas. The mechanisms by which different monocyte subsets support the growth of lymphoma is poorly understood. Using a pre-clinical mouse model of B cell non-Hodgkin's lymphoma (B-NHL), we investigated the impact of tumor progression on circulating monocyte levels, subset distribution and their activity, with a focus on immune suppression.

HPV16E7-Induced Hyperplasia Promotes CXCL9/10 Expression and Induces CXCR3 T-Cell Migration to Skin.

Chemokines regulate tissue immunity by recruiting specific subsets of immune cells. Mice expressing the E7 protein of human papilloma virus 16 as a transgene from a keratin 14 promoter (K14.E7) show increased epidermal and dermal lymphocytic infiltrates, epidermal hyperplasia, and suppressed local immunity.

Natural killer cell metabolism.

Natural killer (NK) cells are a critical component in the innate immune response against disease. NK cell function is tightly regulated by specific cytokine and activation/inhibitory receptor signalling, leading to diverse effector responses. Like all living cells, energy metabolism is a fundamental requirement for NK cell activation and survival.

β-Adrenergic Signaling Impairs Antitumor CD8 T-cell Responses to B-cell Lymphoma Immunotherapy.

β-Adrenergic receptor (βAR) signaling regulates many physiological processes, including immune system responses. There is growing evidence also for βAR-induced modulation of cancer growth and metastasis. In the Eμ-myc mouse model of B-cell lymphoma, we investigated the effects of chronically elevated βAR signaling on lymphoma progression and antitumor immunity, as well as the impact on cancer immunotherapy.

Invariant Natural Killer T Cells in Immune Regulation of Blood Cancers: Harnessing Their Potential in Immunotherapies.

Invariant natural killer T (iNKT) cells are a unique innate T lymphocyte population that possess cytolytic properties and profound immunoregulatory activities. iNKT cells play an important role in the immune surveillance of blood cancers. They predominantly recognize glycolipid antigens presented on CD1d, but their activation and cytolytic activities are not confined to CD1d expressing cells.

Therapeutic Efficacy of 4-1BB Costimulation Is Abrogated by PD-1 Blockade in a Model of Spontaneous B-cell Lymphoma.

Combinations of mAbs that target various components of T-cell activation/inhibition may work synergistically to improve antitumor immunity against cancer. In this study, we investigated the therapeutic potential of combining an anticancer vaccination strategy with antibodies targeting an immune stimulatory (4-1BB) and immune inhibitory (PD-1) receptor, in a preclinical model of spontaneously arising c-Myc-driven B-cell lymphoma. In Eμ-myc transgenic mice, we reveal that 4-1BB agonistic mAb treatment alone was sufficient to drive antitumor immunity and prevent disease progression in 70% of mice.

Control of B-cell lymphoma by therapeutic vaccination and acquisition of immune resistance is independent of direct tumour IFN-gamma signalling.

Immunomodulatory therapies can effectively control haematological malignancies by promoting antitumour immunity. Previously, we reported transient growth of poorly immunogenic murine non-Hodgkin B-cell lymphomas (B-NHL) by targeting natural killer T (NKT) cells with a therapeutic vaccine approach. Therapeutic efficacy was highly dependent on the ability of the vaccine to provoke rapid interferon-gamma (IFNγ) production from NKT and NK cells.

Molecular and Translational Classifications of DAMPs in Immunogenic Cell Death.

The immunogenicity of malignant cells has recently been acknowledged as a critical determinant of efficacy in cancer therapy. Thus, besides developing direct immunostimulatory regimens, including dendritic cell-based vaccines, checkpoint-blocking therapies, and adoptive T-cell transfer, researchers have started to focus on the overall immunobiology of neoplastic cells. It is now clear that cancer cells can succumb to some anticancer therapies by undergoing a peculiar form of cell death that is characterized by an increased immunogenic potential, owing to the emission of the so-called "damage-associated molecular patterns" (DAMPs).

Langerhans cell homeostasis and activation is altered in hyperplastic human papillomavirus type 16 E7 expressing epidermis.

It has previously been shown that expression of human papillomavirus type 16 (HPV) E7 in epidermis causes hyperplasia and chronic inflammation, characteristics of pre-malignant lesions. Importantly, E7-expressing epidermis is strongly immune suppressed and is not rejected when transplanted onto immune competent mice. Professional antigen presenting cells are considered essential for initiation of the adaptive immune response that results in graft rejection.

NKT cell-targeted vaccination plus anti-4-1BB antibody generates persistent CD8 T cell immunity against B cell lymphoma.

Harnessing the immune adjuvant properties of natural killer T (NKT) cells is an effective strategy to generate anticancer immunity. The objective of this study was to increase the potency and durability of vaccine-induced immunity against B cell lymphoma by combining α-galactosylceramide (α-GalCer)-loaded tumor cell vaccination with an agonistic antibody targeting the immune checkpoint molecule 4-1BB (CD137). We observed potent synergy when combining vaccination and anti-4-1BB antibody treatment resulting in significantly enhanced survival of mice harboring Eμ-myc tumors, including complete eradication of lymphoma in over 50% of mice.

Interleukin-17A Promotes Arginase-1 Production and 2,4-Dinitrochlorobenzene-Induced Acute Hyperinflammation in Human Papillomavirus E7 Oncoprotein-Expressing Skin.

Human papillomaviruses (HPVs) have evoked numerous mechanisms to subvert host innate immunity and establish a local immunosuppressive environment to facilitate persistent virus infection. Topical application of 2,4-dinitrochlorobenzene (DNCB) was speculated to overcome this immunosuppressive environment and was employed in the immunotherapy of HPV-associated lesions. We have previously shown that DNCB treatment of skin expressing HPV16.

IL-17 suppresses immune effector functions in human papillomavirus-associated epithelial hyperplasia.

Persistent infection with high-risk human papillomaviruses (HPV) causes epithelial hyperplasia that can progress to cancer and is thought to depend on immunosuppressive mechanisms that prevent viral clearance by the host. IL-17 is a cytokine with diverse functions in host defense and in the pathology of autoimmune disorders, chronic inflammatory diseases, and cancer. We analyzed biopsies from patients with HPV-associated cervical intraepithelial neoplasia grade 2/3 and murine skin displaying HPV16 E7 protein-induced epithelial hyperplasia, which closely models hyperplasia in chronic HPV lesions.

IL-18, but not IL-12, induces production of IFN-γ in the immunosuppressive environment of HPV16 E7 transgenic hyperplastic skin.

IFN-γ has a central role in the defense against infections and cancer. More recently, however, IFN-γ has also been reported to have immunosuppressive effects in models of autoimmune disease, melanoma, and premalignant skin disease. Although IL-12 and IL-18 are critical inducers of IFN-γ during infection, the mechanisms that induce IFN-γ in an immunosuppressive context are unknown.

Combining low-dose or metronomic chemotherapy with anticancer vaccines: A therapeutic opportunity for lymphomas.

Therapeutic vaccination is regarded as a promising strategy against multiple hematological malignancies including lymphoma. However, this approach alone possesses limited potential for the treatment of established tumors. As several anticancer regimens relies on the combination of multiple drugs, it is reasonable to predict that also cancer vaccination will be most effective in the context of multimodal approaches.

CCL2/CCR2-dependent recruitment of functional antigen-presenting cells into tumors upon chemotherapy.

The therapeutic efficacy of anthracyclines relies, at least partially, on the induction of a dendritic cell- and T-lymphocyte-dependent anticancer immune response. Here, we show that anthracycline-based chemotherapy promotes the recruitment of functional CD11b(+)CD11c(+)Ly6C(high)Ly6G(-)MHCII(+) dendritic cell-like antigen-presenting cells (APC) into the tumor bed, but not into lymphoid organs. Accordingly, draining lymph nodes turned out to be dispensable for the proliferation of tumor antigen-specific T cells within neoplastic lesions as induced by anthracyclines.

An intact immune system is required for the anticancer activities of histone deacetylase inhibitors.

Cell-intrinsic effects such as induction of apoptosis and/or inhibition of cell proliferation have been proposed as the major antitumor responses to histone deacetylase inhibitors (HDACi). These compounds can also mediate immune-modulatory effects that may contribute to their anticancer effects. However, HDACi can also induce anti-inflammatory, and potentially immunosuppressive, outcomes.

Anticancer chemotherapy-induced intratumoral recruitment and differentiation of antigen-presenting cells.

The therapeutic efficacy of anthracyclines relies on antitumor immune responses elicited by dying cancer cells. How chemotherapy-induced cell death leads to efficient antigen presentation to T cells, however, remains a conundrum. We found that intratumoral CD11c(+)CD11b(+)Ly6C(hi) cells, which displayed some characteristics of inflammatory dendritic cells and included granulomonocytic precursors, were crucial for anthracycline-induced anticancer immune responses.