Enterotoxigenic Bacteroides fragilis (ETBF), a human commensal and candidate pathogen in colorectal cancer (CRC), is a potent initiator of interleukin-17 (IL-17)-dependent colon tumorigenesis in Min
...mice. We examined the role of IL-17 and ETBF on the differentiation of myeloid cells into myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages, which are known to promote tumorigenesis. The myeloid compartment associated with ETBF-induced colon tumorigenesis in Min mice was defined using flow cytometry and gene expression profiling. Cell-sorted immature myeloid cells were functionally assayed for inhibition of T-cell proliferation and inducible nitric oxide synthase expression to delineate MDSC populations. A comparison of ETBF infection with that of other oncogenic bacteria (Fusobacterium nucleatum or pks
Escherichia coli) revealed a specific, ETBF-associated colonic immune infiltrate. ETBF-triggered colon tumorigenesis is associated with an IL-17-driven myeloid signature characterized by subversion of steady-state myelopoiesis in favor of the generation of protumoral monocytic-MDSCs (MO-MDSCs). Combined action of the B. fragilis enterotoxin BFT and IL-17 on colonic epithelial cells promoted the differentiation of MO-MDSCs, which selectively upregulated Arg1 and Nos2, produced NO, and suppressed T-cell proliferation. Evidence of a pathogenic inflammatory signature in humans colonized with ETBF may allow for the identification of populations at risk for developing colon cancer.
Dendritic cells (DCs) are professional antigen-presenting cells (APCs) specialized in the stimulation of naïve T lymphocytes, which are key components of antiviral and antitumor immunity. DCs are ...'sentinels' of the immune system endowed with the mission to (1) sense invading pathogens as well as any form of tissue distress and (2) alert the effectors of the immune response. They represent a very heterogeneous population including subsets characterized by their anatomical locations and specific missions. Beyond their unique APC features, DCs exhibit a large array of effector functions that play critical roles in the induction and regulation of the cell-mediated as well as humoral immune responses. In the course of the antitumor immune response, DCs are unique in engulfing tumor cells killed by natural killer (NK) cells and cross-presenting tumor-associated antigens to cytotoxic T lymphocytes (CTLs). However, while DCs mediate antitumor immune responses by stimulating tumor-specific CTLs and NK cells, direct tumoricidal mechanisms have been recently evoked. This review addresses the other face of DCs to directly deliver apoptotic signals to stressed cells, their role in tumor cell death, and its implication in the design of DC-based cancer immunotherapies.
Natural killer (NK) cells and dendritic cells (DCs) are, respectively, central components of innate and adaptive immune responses. We describe here a third DC lineage, termed interferon-producing ...killer DCs (IKDCs), distinct from conventional DCs and plasmacytoid DCs and with the molecular expression profile of both NK cells and DCs. They produce substantial amounts of type I interferons (IFN) and interleukin (IL)-12 or IFN-γ, depending on activation stimuli. Upon stimulation with CpG oligodeoxynucleotides, ligands for Toll-like receptor (TLR)-9, IKDCs kill typical NK target cells using NK-activating receptors. Their cytolytic capacity subsequently diminishes, associated with the loss of NKG2D receptor (also known as Klrk1) and its adaptors, Dap10 and Dap12. As cytotoxicity is lost, DC-like antigen-presenting activity is gained, associated with upregulation of surface major histocompatibility complex class II (MHC II) and costimulatory molecules, which formally distinguish them from classical NK cells. In vivo, splenic IKDCs preferentially show NK function and, upon systemic infection, migrate to lymph nodes, where they primarily show antigen-presenting cell activity. By virtue of their capacity to kill target cells, followed by antigen presentation, IKDCs provide a link between innate and adaptive immunity.
Although they are considered as antigen-presenting cells, the role of antigen-unspecific B lymphocytes in antigen presentation and T-lymphocyte stimulation remains controversial. In this paper, we ...tested the capacity of normal human peripheral activated B cells to stimulate T cells using melanoma antigens or melanoma cell lysates. B lymphocytes activated through CD40 ligation and then pulsed with tumor antigens efficiently processed and presented MHC class II-restricted peptides to specific CD4(+) T-cell clones. This suggests that CD40-activated B cells have the functional and molecular competence to present MHC class II epitopes when pulsed with exogenous antigens, thereby making them a relevant source of antigen-presenting cells to generate T cells. To test this hypothesis, CD40-activated B cells were pulsed with a lysate prepared from melanoma cells and used to stimulate peripheral autologous T cells. Interestingly, T cells specific to melanoma antigens were generated. Additional analysis of these T-cell clones revealed that they recognized MHC class II-restricted epitopes from tyrosinase, a known melanoma tumor antigen. The efficient antigen presentation by antigen-unspecific activated B cells was correlated with a down-regulation in the expression of HLA-DO, a B cell-specific protein known to interfere with HLA-DM function. Because HLA-DM is important in MHC class II peptide loading, the observed decrease in HLA-DO may partially explain the enhanced antigen presentation after B-cell activation. Results globally suggest that when they are properly activated, antigen-unspecific B-lymphocytes can present exogenous antigens by MHC class II molecules and stimulate peripheral antigen-specific T cells. Antigen presentation by activated B cells could be exploited for immunotherapy by allowing the in vitro generation of T cells specific against antigens expressed by tumors or viruses.
B7-DC, one of the recently described B7 family members, has the capacity to inhibit T cell responses via engagement of the immunoreceptor tyrosine-based inhibitory motif-containing inhibitory PD-1 ...receptor as well as enhance responses via an as yet unidentified costimulatory receptor. B7-DC is highly homologous to a coinhibitory B7 family member, B7-H1, which also binds PD-1. It is currently unclear which B7-DC function-costimulation or inhibition-predominates in vivo. To study in vivo functions of B7-DC, we evaluated immune responses in B7-DC knockout (KO) mice. Although not eliminated, interferon-gamma (IFN-gamma) production by CD4 T cells and IFN-gamma-dependent humoral responses were reduced in B7-DC KO mice relative to wild type mice. Antigen-specific CD8 T cell responses and cytotoxic T lymphocyte (CTL) activity were also diminished in B7-DC KO mice. Hepatic tumors grew more quickly in B7-DC KO mice, associated with a decrease in intrahepatic tumor-specific CD8 T cells. These results highlight the contrasting in vivo roles of B7-DC and B7-H1 and indicate that B7-DC functions as a tuning molecule, selectively augmenting T helper 1 and CTL responses.
Cancer results from a tumor cell intrinsic dysregulation of oncogenes, tumor suppressor and stability genes as well as from the avoidance of immunosurveillance. A complex network of cellular ...interactions allows one to mount cognate anti-tumor immune responses. Recently, discoveries have been made regarding the links between innate and cognate antitumor immunity eliciting protective T-cell responses. The intricate differentiation pathway, whereby dendritic cells can efficiently mature in the tumor microenvironment, appears crucial for the priming of T cells. Transformed cells might deliver danger signals directly to the dendritic cell. Alternatively, other cell types belonging to the innate immune system can sense transformed cells through a specific set of receptors and then interact with dendritic cells to modulate their activation state. A novel subset of innate effector cells called interferon-producing killer dendritic cells are multitasking chimeras that can recognize and kill transformed cells, and undergo a maturation state of antigen presentation. Also, evidence has been produced suggesting that cell death promoted by conventional chemotherapy or radiotherapy might elicit interactions between the innate and the cognate immune system that result in anti-tumor immune responses.
B7-DC is a recently discovered member of the B7 family that binds to PD-1 and is selectively expressed by dendritic cells (DCs). It has been shown to either costimulate or inhibit T cell responses. ...To assess the role of B7-DC in DC-T cell interactions, DCs from B7-DC knockout (KO) mice were generated and compared with DCs from wild-type (WT) and B7-1/B7-2 double KO mice. B7-1/B7-2-deficient DCs, while strongly diminished in their ability to stimulate naive CD4+ T cells, nonetheless retain partial activity. DCs from B7-DC KO mice are diminished in their ability to activate CD4+ T cells, demonstrating that DC-expressed B7-DC serves a predominantly stimulatory rather than inhibitory function in the initiation of T cell responses. B7-DC costimulates expression of CD40L with faster kinetics than B7-1 and displays potent synergy with B7-1 and B7-2 for T cell proliferation and cytokine production, indicating that these B7 family members work in concert to stimulate T cells. Finally, costimulation with B7-DC alone or in conjunction with B7-1 is PD-1 independent, indicating that B7-DC costimulates T cells via a second receptor.
Preclinical models for the identification of prostate cancer chemoprevention agents are lacking. Based upon the notion that clinically useful chemoprevention agents should exhibit selective activity ...against early stage disease, studies were undertaken to assess whether chemoprevention agents selectively inhibited the growth of early stage prostate cancer, as compared to late stage cancer. First, a series of cell and molecular studies were performed, which, when taken together, validated the use of a panel of prostate cell lines as a model of the different stages of carcinogenesis. Next, therapeutic responsiveness to ten different cytotoxic or chemoprevention agents was evaluated. Chemoprevention agents exhibited selective activity against normal and early transformed prostate tissue, whereas cytotoxic agents were non-specific. Selective activity against early versus advanced prostate cancer cells is identified as a potential screening method for chemoprevention agents.Prostate Cancer and Prostatic Diseases (2001) 4, 81-91
PDF
