The terminology issue for myeloid-derived suppressor cells.
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Animals↗
Biomedical subjects
Vincenzo Bronte
Publications and source records attributed to Vincenzo Bronte.
Nitric oxide, a double edged sword in cancer biology: searching for therapeutic opportunities.
Nitric oxide (NO) is a pleiotropic molecule critical to a number of physiological and pathological processes. The last decade has witnessed major advances in dissecting NO biology and its role in cancer pathogenesis. However, the complexity of the interactions between different levels of NO and several aspects of tumor development/progression has led to apparently conflicting findings. Furthermore, both anti-NO and NO-based anticancer strategies appear effective in several preclinical models. This paradoxical dichotomy is leaving investigators with a double challenge: to determine the net impact of NO on cancer behavior and to define the therapeutic role of NO-centered anticancer strategies. Only a comprehensive and dynamic view of the cascade of molecular and cellular events underlying tumor biology and affected by NO will allow investigators to exploit the potential antitumor properties of drugs interfering with NO metabolism. Available data suggest that NO should be considered neither a universal target nor a magic bullet, but rather a signal transducer to be modulated according to the molecular makeup of each individual cancer and the interplay with conventional antineoplastic agents.
Animals↗
Phosphodiesterase-5 inhibition augments endogenous antitumor immunity by reducing myeloid-derived suppressor cell function.
Phosphodiesterase-5 (PDE5) inhibitors (sildenafil, tadalafil, and vardenafil) are agents currently in clinical use for nonmalignant conditions. We report the use of PDE5 inhibitors as modulators of the antitumor immune response. In several mouse tumor models, PDE5 inhibition reverses tumor-induced immunosuppressive mechanisms and enables a measurable antitumor immune response to be generated that substantially delays tumor progression. In particular, sildenafil, down-regulates arginase 1 and nitric oxide synthase-2 expression, thereby reducing the suppressive machinery of CD11b+/Gr-1+ myeloid-derived suppressor cells (MDSCs) recruited by growing tumors. By removing these tumor escape mechanisms, sildenafil enhances intratumoral T cell infiltration and activation, reduces tumor outgrowth, and improves the antitumor efficacy of adoptive T cell therapy. Sildenafil also restores in vitro T cell proliferation of peripheral blood mononuclear cells from multiple myeloma and head and neck cancer patients. In light of the recent data that enzymes mediating MDSC-dependent immunosuppression in mice are active also in humans, these findings demonstrate a potentially novel use of PDE5 inhibitors as adjuncts to tumor-specific immune therapy.
3',5'-Cyclic-GMP Phosphodiesterases↗
Leukocyte infiltration in cancer creates an unfavorable environment for antitumor immune responses: a novel target for therapeutic intervention.
The interaction between tumor cells and the nearby environment is being actively investigated to explore how this interplay affects the initiation and progression of cancer. Host-tumor relationship results in the production of pro-inflammatory cytokines and chemokines that promote the recruitment of leukocytes within and around developing neoplasms. Cancer cells, together with newly recruited tumor-infiltrating cells, can also activate fibroblast and vascular responses, thus resulting in a chronic microenvironment perturbation. In this complex scenario, interactions between innate and adaptive immune cells can be disturbed, leading to a failure of immune-mediated tumor recognition and destruction. On the basis of the recent awareness about tumor promotion and immune deregulation by immune/inflammatory cells, novel anti-cancer strategies can be exploited.
Animals↗
Tumors induce a subset of inflammatory monocytes with immunosuppressive activity on CD8+ T cells.
Active suppression of tumor-specific T lymphocytes can limit the efficacy of immune surveillance and immunotherapy. While tumor-recruited CD11b+ myeloid cells are known mediators of tumor-associated immune dysfunction, the true nature of these suppressive cells and the fine biochemical pathways governing their immunosuppressive activity remain elusive. Here we describe a population of circulating CD11b+IL-4 receptor alpha+ (CD11b+IL-4Ralpha+), inflammatory-type monocytes that is elicited by growing tumors and activated by IFN-gamma released from T lymphocytes. CD11b+IL-4Ralpha+ cells produced IL-13 and IFN-gamma and integrated the downstream signals of these cytokines to trigger the molecular pathways suppressing antigen-activated CD8+ T lymphocytes. Analogous immunosuppressive circuits were active in CD11b+ cells present within the tumor microenvironment. These suppressor cells challenge the current idea that tumor-conditioned immunosuppressive monocytes/macrophages are alternatively activated. Moreover, our data show how the inflammatory response elicited by tumors had detrimental effects on the adaptive immune system and suggest novel approaches for the treatment of tumor-induced immune dysfunctions.
Animals↗
Toward the identification of a tolerogenic signature in IDO-competent dendritic cells.
Although much is known about the transcriptional profiles of dendritic cells (DCs) during maturation, the molecular switches critical for the induction of a tolerogenic program in DC subsets are still obscure. We examined the gene-expression profiles of murine splenic CD8+ DCs rendered highly tolerogenic by interferon-gamma (IFN-gamma), which activates the enzyme indoleamine 2,3-dioxygenase (IDO, encoded by Indo) and thus initiates the immunosuppressive pathway of tryptophan catabolism. By examining the expression of a series of relevant genes in IDO+ compared with IDO- DCs, we found consistent and selective association of the IDO-competent phenotype with down-modulation of the Tyrobp gene, encoding the signaling adapter DAP12, which typically associates with activating receptors. Down-modulation of Tyrobp involved IFN consensus sequence binding protein (ICSBP), a transcription factor also known as IRF-8. In murine and human monocyte-derived DCs, silencing DAP12 expression imparted IDO functional competence to IDO- cells, whereas silencing IRF-8 in IDO+ counterparts abolished IDO expression and function. Thus, IRF-8 is required in tolerogenic DCs for the positive regulation of Indo and the negative regulation of Tyrobp. Overall, these studies reveal the occurrence of a simple and evolutionarily conserved code in the control of tolerance by an ancestral metabolic enzyme.
Adaptor Proteins, Signal Transducing↗
Myeloid suppressor cells in cancer: recruitment, phenotype, properties, and mechanisms of immune suppression.
Growing tumors acquire the ability to resist immune recognition and immune-mediated injury. Among several mechanisms, mouse and human tumors share the ability to alter the normal hematopoiesis, leading to accumulation of cells of the myelo-monoctytic lineage at the tumor site and in different primary and secondary lymphoid organs. These cells aid tumor development by providing molecules and factors essential for tumor growth and neovascularization but also exert a profound inhibitory activity on both tumor-specific and nonspecific T lymphocytes. The present article summarizes recent findings on the interaction between developing cancers and these recently described "myeloid suppressor cells".
Animals↗
Cancer immunotherapy based on killing of Salmonella-infected tumor cells.
A major obstacle for the development of effective immunotherapy is the ability of tumors to escape the immune system. The possibility to kill tumor cells because they are recognized as infected rather than as malignant could help overcome immune escape mechanisms. Here we report a conceptually new approach of cancer immunotherapy based on in vivo infection of tumors and killing of infected tumor cells. Attenuated but still invasive, Salmonella typhimurium can be successfully exploited to invade melanoma cells that can present antigenic determinants of bacterial origin and become targets for anti-Salmonella-specific T cells. However, to fully appreciate the anticancer therapeutic properties of S. typhimurium, tumor-bearing mice need to be vaccinated against S. typhimurium before intratumoral Salmonella injection. Tumor infection when coupled to anti-Salmonella vaccination leads to 50% to 100% tumor-free mice with a better outcome on larger tumors. Invasive Salmonella also exert an indirect toxic effect on tumor cells through the recruitment of inflammatory cells and the cross-presentation of tumor antigens, which allow induction of tumor-specific immune response. This is effective in retarding the growth of untreated established distant tumors and in protecting the mice from subsequent tumor challenges.
Animals↗
Boosting antitumor responses of T lymphocytes infiltrating human prostate cancers.
Immunotherapy may provide valid alternative therapy for patients with hormone-refractory metastatic prostate cancer. However, if the tumor environment exerts a suppressive action on antigen-specific tumor-infiltrating lymphocytes (TIL), immunotherapy will achieve little, if any, success. In this study, we analyzed the modulation of TIL responses by the tumor environment using collagen gel matrix-supported organ cultures of human prostate carcinomas. Our results indicate that human prostatic adenocarcinomas are infiltrated by terminally differentiated cytotoxic T lymphocytes that are, however, in an unresponsive status. We demonstrate the presence of high levels of nitrotyrosines in prostatic TIL, suggesting a local production of peroxynitrites. By inhibiting the activity of arginase and nitric oxide synthase, key enzymes of L-arginine metabolism that are highly expressed in malignant but not in normal prostates, reduced tyrosine nitration and restoration of TIL responsiveness to tumor were achieved. The metabolic control exerted by the tumor on TIL function was confirmed in a transgenic mouse prostate model, which exhibits similarities with human prostate cancer. These results identify a novel and dominant mechanism by which cancers induce immunosuppression in situ and suggest novel strategies for tumor immunotherapy.
Adenocarcinoma↗
Nitroaspirin corrects immune dysfunction in tumor-bearing hosts and promotes tumor eradication by cancer vaccination.
Active suppression of tumor-specific T lymphocytes can limit the immune-mediated destruction of cancer cells. Of the various strategies used by tumors to counteract immune attacks, myeloid suppressors recruited by growing cancers are particularly efficient, often resulting in the induction of systemic T lymphocyte dysfunction. We have previously shown that the mechanism by which myeloid cells from tumor-bearing hosts block immune defense strategies involves two enzymes that metabolize L-arginine: arginase and nitric oxide (NO) synthase. NO-releasing aspirin is a classic aspirin molecule covalently linked to a NO donor group. NO aspirin does not possess direct antitumor activity. However, by interfering with the inhibitory enzymatic activities of myeloid cells, orally administered NO aspirin normalized the immune status of tumor-bearing hosts, increased the number and function of tumor-antigen-specific T lymphocytes, and enhanced the preventive and therapeutic effectiveness of the antitumor immunity elicited by cancer vaccination. Because cancer vaccines and NO aspirin are currently being investigated in independent phase I/II clinical trials, these findings offer a rationale to combine these treatments in subjects with advanced neoplastic diseases.
Animals↗
Regulation of immune responses by L-arginine metabolism.
L-Arginine is an essential amino acid for birds and young mammals, and it is a conditionally essential amino acid for adult mammals, as it is important in situations in which requirements exceed production, such as pregnancy. Recent findings indicate that increased metabolism of L-arginine by myeloid cells can result in the impairment of lymphocyte responses to antigen during immune responses and tumour growth. Two enzymes that compete for L-arginine as a substrate - arginase and nitric-oxide synthase - are crucial components of this lymphocyte-suppression pathway, and the metabolic products of these enzymes are important moderators of T-cell function. This Review article focuses on the relevance of L-arginine metabolism by myeloid cells for immunity under physiological and pathological conditions.
Animals↗
Therapeutic effectiveness of recombinant cancer vaccines is associated with a prevalent T-cell receptor alpha usage by melanoma-specific CD8+ T lymphocytes.
Definition of immune variables that correlate with the antitumor activity of cancer vaccines is critical for monitoring immunotherapy protocols. To define surrogate end points predictive of the therapeutic efficacy of recombinant vaccines based on melanoma antigen tyrosinase-related protein (TRP)-2, we evaluated several properties of antigen-specific CD8(+) T lymphocytes in single mice undergoing either prophylactic or therapeutic immunization. Predictive markers for the efficacy of genetic vaccination were identified in the prophylactic model used. Interestingly, the number of tetramer(+) CD8(+) T lymphocytes expanded in vitro after a single cycle of stimulation with the immunodominant TRP-2 peptide was of the highest predictive value. In the therapeutic model, no variable examined at a single mouse level predicted the long-term therapeutic effect. Mice that survived did not show the highest expansion of antigen-specific lymphocytes or the more functionally active effectors, ex vivo or after in vitro culture with the peptide antigen. Successful therapy correlated strictly with the skewing of the T-cell receptor repertoire of tetramer-sorted, TRP-2-specific CD8(+) T lymphocytes, which showed a preferential alpha chain usage with a common CDR3 region.
Adenoviridae↗
High-dose granulocyte-macrophage colony-stimulating factor-producing vaccines impair the immune response through the recruitment of myeloid suppressor cells.
Tumor vaccines have shown promise in early clinical trials. Among them, tumor cells genetically engineered to secrete biologically active granulocyte-macrophage colony-stimulating factor (GM-CSF) can generate a systemic antitumor immune response. Although the minimal required GM-CSF dose produced by modified tumor cells to achieve a measurable antitumor effect is well known, no data examined whether an upper therapeutic limit may exist for this vaccination strategy. Because recent data demonstrate an immunosuppressive effect of GM-CSF produced by growing tumors, we thus sought to determine whether high GM-CSF doses administered in a vaccine formulation could impair antitumor immunity. Using a vaccine strategy involving a GM-CSF-producing bystander cell line (B78H1-GM) admixed with autologous tumor, we assessed the impact of varying doses of GM-CSF while maintaining a constant antigen dose. Our results defined a threshold above which a GM-CSF-based vaccine not only lost its efficacy, but more importantly for its clinical implications resulted in substantial immunosuppression in vivo. Above this threshold, GM-CSF induced Gr1+/CD11b+ myeloid suppressor cells that substantially impaired antigen-specific T-cell responses and adversely affected antitumor immune responses in vivo. The dual effects of GM-CSF are mediated by the systemic and not local concentration of this cytokine. Myeloid suppressor cell-induced immunosuppression is mediated by nitric oxide production via inducible nitric oxide synthase (iNOS) because the specific iNOS inhibitor, l-NMMA, restored antigen-specific T-cell responsiveness in vitro. Taken together, our data demonstrated the negative impact of supra-therapeutic vaccine doses of GM-CSF and underscored the importance of identifying these critical variables in an effort to increase the therapeutic efficacy of tumor vaccines.
Animals↗
CpG-Oligodeoxynucleotides activate tyrosinase-related protein 2-specific T lymphocytes but do not lead to a protective tumor-specific memory response.
PURPOSE: Peritumoral CpG-oligodeoxynucleotide (ODN) treatment has been successful in tumor mouse models expressing strong antigens to induce activation of tumor-specific CD8+ T lymphocytes which contribute to the control of tumor growth. To get near to clinical reality, the tumor-specific CD8+ response was investigated in mice bearing the weakly immunogenic B16 melanoma tumor and using the melanocyte differentiation tyrosinase-related protein 2 (TRP-2) as a tracking antigen. METHODS: The expansion and activation of TRP-2-specific T lymphocytes by CpG-ODNs was analyzed by tetramer staining and IFN-gamma production assays, while the activity of these cells in both memory and primary response was evaluated in vivo. RESULTS: After CpG-ODN treatment, the number of TRP-2 tetramer-stained CD8+ T lymphocytes was not significantly modified, but these cells produced higher levels of interferon gamma (IFN-gamma) in response to the antigen than those from untreated mice. Mice possessing these activated T lymphocytes, when evaluated for their antitumor memory response, showed marginal protection against intravenous (i.v.) and subcutaneous (s.c.) tumor rechallenge. These cells were not crucial for the control of primary tumor growth since strong reduction of subcutaneous tumor was observed after CpG-ODN treatment in both CD8+ T cell depleted or nondepleted mice. On the contrary, NK cell depletion markedly reduced CpG-ODN-induced tumor growth inhibition. CONCLUSIONS: Altogether, these data indicate the CpG treatment activates tumor-reactive effector CD8+ T lymphocytes, but, paralleling recent clinical observations, our model indicates that the mere activation of antitumor T cells is insufficient to result in a clinical response.
Animals↗
Part I: Vaccines for solid tumours.
Active specific immunotherapy holds great potential in the search for new therapeutic approaches for patients with cancer. Much preclinical and clinical evidence has shown that the immune system can be polarised against malignant cells by several vaccination strategies. Although no anticancer vaccine can be recommended outside clinical trials at present, tumour response and immunological findings in animals and humans should prompt researchers to investigate further the potential of this biotherapy. We summarise strategies for cancer vaccines so far implemented in the clinical setting, report the results of more than 200 clinical trials published over the past two decades, and discuss insights into preclinical tumour immunology that might aid the design of the next generation of cancer vaccines.
Antigens, Neoplasm↗
Cancer vaccines: pessimism in check.
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Antigens, Neoplasm↗
Effective genetic vaccination with a widely shared endogenous retroviral tumor antigen requires CD40 stimulation during tumor rejection phase.
Endogenous retrovirus (ERV) products are recognized by T lymphocytes in mice and humans. As these Ags are preferentially expressed by neoplastic tissues, they might represent an ideal target for active immunization by genetic vaccination. However, i.m. inoculation of plasmid DNA encoding mouse gp70 or p15E, two products of the env gene of an endogenous murine leukemia virus, elicited a weak Ag-specific T lymphocyte response and resulted in partial protection from challenge with mouse tumors possessing these Ags. Depletion experiments showed that CD8(+), but not CD4(+), T lymphocytes were crucial for the antitumor activity of the vaccines. Systemic administration of agonistic anti-CD40 mAb increased the therapeutic potential of genetic vaccination, but only when given during the tumor rejection phase and not at the time of immunization. This effect correlated with a dramatic increase in the number of ERV-specific CD8(+) T lymphocytes. Adjuvant activity of CD40 agonists thus seems to be relevant to enhance the CD8(+) T cell-dependent response in tumor-bearing hosts, suggesting that sustaining tumor-specific T lymphocyte survival in subjects undergoing vaccination might be a key event in the successful vaccination with weak tumor Ags.
Animals↗
Derangement of immune responses by myeloid suppressor cells.
In tumor-bearing mice and cancer patients, tumor progression is often associated with altered hematopoiesis leading to the accumulation of myeloid cells. Extensive studies in preclinical models indicate that these cells share the CD11b and the Gr-1 markers, possess a mixed mature-immature myeloid phenotype, and are responsible for the induction of T-cell dysfunctions, both tumor-specific and nonspecific. Moreover, CD11b(+)Gr-1(+) myeloid cells are described under different unrelated situations associated with temporary impairment of the T-lymphocyte reactivity. This review examines recent findings on the nature, properties, and mechanisms of action of these myeloid suppressor cells (MSCs).
Animals↗