Colorectal cancer (CRC), a multi-step malignancy showing increasing incidence in today’s societies, represents an important worldwide health issue. Exogenous factors, such as lifestyle, diet, ...nutrition, environment and microbiota, contribute to CRC pathogenesis, also influencing non neoplastic cells, including immune cells. Several immune dysfunctions were described in CRC patients at different disease stages. Many studies underline the role of microbiota, obesity-related inflammation, diet and host reactive cells, including dendritic cells (DC), in CRC pathogenesis. Here, we focused on DC, the main cells linking innate and adaptive anti-cancer immunity. Variations in the number and phenotype of circulating and tumor-infiltrating DC have been found in CRC patients and correlated with disease stages and progression. A critical review of DC-based clinical studies and of recent advances in cancer immunotherapy leads to consider new strategies for combining DC vaccination strategies with check-point inhibitors, thus opening perspectives for a more effective management of this neoplastic disease.
Type I interferons (IFN-I) are antiviral cytokines endowed with multiple biological actions, including antitumor activity. Studies in mouse models and cancer patients support the concept that ...endogenous IFN-I play important roles in the control of tumor development and growth as well as in response to several chemotherapy/radiotherapy treatments. While IFN-I signatures in the tumor microenvironment are often considered as biomarkers for a good prognostic response to antitumor therapies, prolonged IFN-I signaling can lead to immune dysfunction, thereby promoting pathogen or tumor persistence, thus revealing the "Janus face" of these cytokines in cancer control, likely depending on timing, tissue microenvironment and cumulative levels of IFN-I signals. Likewise, IFN-I exhibit different and even opposite effects on obesity, a pathologic condition linked to cancer development and growth. As an example, evidence obtained in mouse models shows that localized expression of IFN-I in the adipose tissue results in inhibition of diet-induced obesity, while hyper-production of these cytokines by specialized cells such as plasmacytoid dendritic cells in the same tissue, can induce systemic inflammatory responses leading to obesity. Further studies in mouse models and humans should reveal the mechanisms by which IFN-I can regulate both tumor growth and obesity and to understand the role of factors such as genetic background, diet and microbioma in shaping the production and action of these cytokines under physiological and pathological conditions.
Highlights • Endogenous IFN-I plays a role in the innate control of tumor growth. • IFN-α acts as inducer for the differentiation/activation of dendritic cells. • IFN-I is crucial in linking innate ...and adaptive immunity. • IFN-α can act as a vaccine adjuvant.
Abstract
The type I interferons are central to a vast array of immunological functions. The production of these immune-modulatory molecules is initiated at the early stages of the innate immune ...responses and, therefore, plays a dominant role in shaping downstream events in both innate and adaptive immunity. Indeed, the major role of IFN-α/β is the induction of priming states, relevant for the functional differentiation of T lymphocyte subsets. Among T-cell subtypes, the CD4+CD25+Foxp3+ T regulatory cells (Tregs) represent a specialized subset of CD4+ T cells with a critical role in maintaining peripheral tolerance and immune homeostasis. Although the role of type I interferons in maintaining the function of thymus-derived Tregs has been previously described, the direct contribution of these innate factors to peripheral Treg (pTreg) and induced Treg (iTreg) differentiation and suppressive function is still unclear. We now show that, under tolerogenic conditions, IFN-α/β play a critical role in antigen-specific and also polyclonal naive CD4+ T-cell conversion into peripheral antigen-specific CD4+CD25+Foxp3+ Tregs and inhibit CD4+ T helper (Th) cell expansion in mice. While type I interferons sustain the expression and the activation of the transcription master regulators Foxp3, Stat3 and Stat5, these innate molecules reciprocally inhibit Th17 cell differentiation. Altogether, these results indicate a new pivotal role of IFN-α/β on pTreg differentiation and induction of peripheral tolerance, which may have important implications in the therapeutic control of inflammatory disorders, such as of autoimmune diseases.
Type I interferons promote Treg cell differentiation
For more than 25 years, dendritic cell (DC) based vaccination has flashily held promises to represent a therapeutic approach for cancer treatment. While the vast majority of studies has focused on ...the use of antigen loaded DC, the intratumoral delivery of unloaded DC aiming at
vaccination has gained much less attention. Such approach grounds on the ability of inoculated DC to internalize and process antigens directly released by tumor (usually in combination with cell-death-inducing agents) to activate broad patient-specific antitumor T cell response. In this review, we highlight the recent studies in both solid and hematological tumors showing promising clinical results and discuss the main pitfalls and advantages of this approach for endogenous cancer vaccination. Lastly, we discuss how
vaccination by DC inoculation may fit with current immunotherapy approaches to expand and prolong patient response.
Type I interferons (IFNs) are pleiotropic cytokines, initially described for their antiviral activity. These cytokines exhibit a long record of clinical use in patients with some types of cancer, ...viral infections and chronic inflammatory diseases. It is now well established that IFN action mostly relies on their ability to modulate host innate and adaptive immune responses. Work in recent years has begun to elucidate the mechanisms by which type I IFNs modify the immune response, and this is now recognized to be due to effects on multiple cell types, including monocytes, dendritic cells (DCs), NK cells, T and B lymphocytes. An ensemble of results from both animal models and in vitro studies emphasized the key role of type I IFNs in the development and function of DCs, suggesting the existence of a natural alliance between these cytokines and DCs in linking innate to adaptive immunity. The identification of IFN signatures in DCs and their dysregulation under pathological conditions will therefore be pivotal to decipher the complexity of this DC-IFN interaction and to better exploit the therapeutic potential of these cells.
Certain chemotherapeutics, particularly cyclophosphamide, can enhance the antitumor efficacy of immunotherapy. A better understanding of the cellular and molecular basis of cyclophosphamide-mediated ...immunomodulation is needed to improve the efficacy of chemoimmunotherapy.
Transcript profiling and flow cytometry were used to explore cyclophosphamide-induced immunoadjuvanticity in patients with hematologic malignancies.
A single high-dose treatment rapidly (1-2 days) induced peripheral blood mononuclear cell (PBMC) transcriptional modulation, leading to reduction of cell-cycle and biosynthetic/metabolic processes and augmentation of DNA damage and cell death pathways (p53 signaling pathway), death-related scavenger receptors, antigen processing/presentation mediators, T-cell activation markers and, noticeably, a type I IFN (IFN-I) signature (OAS1, CXCL10, BAFF, IFITM2, IFI6, IRF5, IRF7, STAT2, UBE2L6, UNC93B1, ISG20L1, TYK2). Moreover, IFN-I-induced proinflammatory mediators (CXCL10, CCL2, IL-8, and BAFF) were increased in patients' plasma. Accordingly, cyclophosphamide induced the expansion/activation of CD14(+)CD16(+) monocytes, of HLA-DR(+), IL-8RA(+), and MARCO(+) monocytes/dendritic cells, and of CD69(+), OX40(+), and IL-8RA(+) lymphocytes.
Altogether, these data identify the cyclophosphamide-induced immunomodulatory factors in humans and indicate that preconditioning chemotherapy may stimulate immunity as a consequence of danger perception associated with blood cell death, through p53 and IFN-I-related mechanisms.
Purpose: Immunotherapy is a promising antitumor strategy, which can be successfully combined with current anticancer treatments, as
suggested by recent studies showing the paradoxical ...chemotherapy-induced enhancement of the immune response. The purpose of
the present work is to dissect the biological events induced by chemotherapy that cooperate with immunotherapy in the success
of the combined treatment against cancer. In particular, we focused on the following: ( a ) cyclophosphamide-induced modulation of several cytokines, ( b ) homeostatic proliferation of adoptively transferred lymphocytes, and ( c ) homing of transferred lymphocytes to secondary lymphoid organs and tumor mass.
Experimental Design: Here, we used the adoptive transfer of tumor-immune cells after cyclophosphamide treatment of tumor-bearing mice as a model
to elucidate the mechanisms by which cyclophosphamide can render the immune lymphocytes competent to induce tumor rejection.
Results: The transfer of antitumor immunity was found to be dependent on CD4 + T cells and on the cooperation of adoptively transferred cells with the host immune system. Of note, tumor-immune lymphocytes
migrated specifically to the tumor only in mice pretreated with cyclophosphamide. Cyclophosphamide treatment also promoted
homeostatic proliferation/activation of transferred B and T lymphocytes. Optimal therapeutic responses to the transfer of
immune cells were associated with the cyclophosphamide-mediated induction of a “cytokine storm” including granulocyte macrophage
colony-stimulating factor, interleukin (IL)-1β, IL-7, IL-15, IL-2, IL-21, and IFN-γ, occurring during the “rebound phase”
after drug-induced lymphodepletion.
Conclusions: The ensemble of these data provides a new rationale for combining immunotherapy and chemotherapy to induce an effective antitumor
response in cancer patients.
Cytokines that are induced by infection may contribute to the initiation of immune responses through their ability to stimulate dendritic cells (DCs). In this paper, we have addressed the role of ...IL-15 in DC activation, investigating its expression by DCs in response to three different signals of infection and examining its ability to stimulate DCs. We report that the expression of both IL-15 and the IL-15 receptor alpha-chain are increased in splenic DCs from mice inoculated with dsRNA (poly(I:C)), LPS, or IFN-alphabeta, and in purified murine splenic DCs treated with IFN-alphabeta in vitro. Furthermore, IL-15 itself was able to activate DCs, as in vivo or in vitro exposure of splenic DCs to IL-15 resulted in an up-regulation of costimulatory molecules, markedly increased production of IFN-gamma by DC and an enhanced ability of DCs to stimulate Ag-specific CD8(+) T cell proliferation. The magnitude of all of the IL-15-induced changes in DCs was reduced in mice deficient for the IFN-alphabeta receptor, suggesting a role for IFN-alphabeta in the stimulation of DCs by IL-15. These results identify IL-15 as a stimulatory cytokine for DCs with the potential for autocrine activity and link its effects to expression of IFN-alphabeta.
Type I interferons (IFN-I) are rapidly induced following infection and play a key role in nonspecific inhibition of virus replication. Here we have investigated the effects of IFN-I on the generation ...of antigen-specific antibody responses. The data show that IFN-I potently enhance the primary antibody response to a soluble protein, stimulating the production of all subclasses of IgG, and induce long-lived antibody production and immunological memory. In addition, endogenous production of IFN-I was shown to be essential for the adjuvant activity of CFA. Finally, IFN-I enhanced the antibody response and induced isotype switching when dendritic cells were the only cell type responding to IFN-I. The data reveal the potent adjuvant activity of IFN-I and their important role in linking innate and adaptive immunity.
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