Resistance to chemoimmunotherapy is a major issue for cancer care. We recently unravelled the role of mitogen-activated protein kinase (MAPK) to limit the antitumor efficacy of such combination. ...Inhibitor of MAPK pathway using mitogen-activated protein kinase (MEK) inhibitor in combination with chemotherapy triggers mitophagy of cancer cells, which induces the release of mitochondrial DNA that interact with Toll Like receptor 9 (TLR9) to promote the production of the chemokine CXCL10. CXCL10 could then turn cold tumor into hot tumor, thus leading to improve efficacy of chemoimmunotherapy.
The receptor NLRP3 is involved in the formation of the NLRP3 inflammasome that activates caspase-1 and mediates the release of interleukin 1β (IL-1β) and IL-18. Whether NLRP3 can shape immunological ...function independently of inflammasomes is unclear. We found that NLRP3 expression in CD4(+) T cells specifically supported a T helper type 2 (TH2) transcriptional program in a cell-intrinsic manner. NLRP3, but not the inflammasome adaptor ASC or caspase-1, positively regulated a TH2 program. In TH2 cells, NLRP3 bound the Il4 promoter and transactivated it in conjunction with the transcription factor IRF4. Nlrp3-deficient TH2 cells supported melanoma tumor growth in an IL-4-dependent manner and also promoted asthma-like symptoms. Our results demonstrate the ability of NLRP3 to act as a key transcription factor in TH2 differentiation.
Natural Killer (NK) cells are innate immune cells that play a pivotal role as first line defenders in the anti-tumor response. To prevent tumor development, NK cells are searching for abnormal cells ...within the body and appear to be key players in immunosurveillance. Upon recognition of abnormal cells, NK cells will become activated to destroy them. In order to fulfill their anti-tumoral function, they rely on the secretion of lytic granules, expression of death receptors and production of cytokines. Additionally, NK cells interact with other cells in the tumor microenvironment. In this review, we will first focus on NK cells’ activation and cytotoxicity mechanisms as well as NK cells behavior during serial killing. Lastly, we will review NK cells’ crosstalk with the other immune cells present in the tumor microenvironment.
Interleukin-1β and Cancer Rébé, Cédric; Ghiringhelli, François
Cancers,
07/2020, Letnik:
12, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Within a tumor, IL-1β is produced and secreted by various cell types, such as immune cells, fibroblasts, or cancer cells. The IL1B gene is induced after “priming” of the cells and a second signal is ...required to allow IL-1β maturation by inflammasome-activated caspase-1. IL-1β is then released and leads to transcription of target genes through its ligation with IL-1R1 on target cells. IL-1β expression and maturation are guided by gene polymorphisms and by the cellular context. In cancer, IL-1β has pleiotropic effects on immune cells, angiogenesis, cancer cell proliferation, migration, and metastasis. Moreover, anti-cancer treatments are able to promote IL-1β production by cancer or immune cells, with opposite effects on cancer progression. This raises the question of whether or not to use IL-1β inhibitors in cancer treatment.
The mechanisms through which regulatory T cells accumulate in lymphoid organs of tumor-bearing hosts remain elusive. Our experiments indicate that the accumulation of CD4+CD25+ regulatory T cells (T ...reg cells) expressing FoxP3 and exhibiting immunosuppressive function originates from the proliferation of naturally occurring CD25+ T cells and requires signaling through transforming growth factor (TGF)-beta receptor II. During tumor progression, a subset of dendritic cells (DCs) exhibiting a myeloid immature phenotype is recruited to draining lymph nodes. This DC subset selectively promotes the proliferation of T reg cells in a TGF-beta-dependent manner in mice and rats. Tumor cells are necessary and sufficient to convert DCs into regulatory cells that secrete bioactive TGF-beta and stimulate T reg cell proliferation. In conclusion, tumor expansion can stimulate T reg cells via a specific DC subset.
Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell-mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T ...reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling innate antitumor immunity. Our experiments indicate that human T reg cells expressed membrane-bound transforming growth factor (TGF)-beta, which directly inhibited NK cell effector functions and down-regulated NKG2D receptors on the NK cell surface. Adoptive transfer of wild-type T reg cells but not TGF-beta-/- T reg cells into nude mice suppressed NK cell-mediated cytotoxicity, reduced NKG2D receptor expression, and accelerated the growth of tumors that are normally controlled by NK cells. Conversely, the depletion of mouse T reg cells exacerbated NK cell proliferation and cytotoxicity in vivo. Human NK cell-mediated tumor recognition could also be restored by depletion of T reg cells from tumor-infiltrating lymphocytes. These findings support a role for T reg cells in blunting the NK cell arm of the innate immune system.
Immune cells in the tumor microenvironment regulate cancer growth. Thus cancer progression is dependent on the activation or repression of transcription programs involved in the ...proliferation/activation of lymphoid and myeloid cells. One of the main transcription factors involved in many of these pathways is the signal transducer and activator of transcription 3 (STAT3). In this review we will focus on the role of STAT3 and its regulation, e.g. by phosphorylation or acetylation in immune cells and how it might impact immune cell function and tumor progression. Moreover, we will review the ability of STAT3 to regulate checkpoint inhibitors.
During tumor growth, angiogenesis is required to ensure oxygen and nutrient transport to the tumor. Vascular endothelial growth factor (VEGF) is the major inducer of angiogenesis and appears to be a ...key modulator of the anti-tumor immune response. Indeed, VEGF modulates innate and adaptive immune responses through direct interactions and indirectly by modulating protein expressions on endothelial cells or vascular permeability. The inhibition of the VEGF signaling pathway is clinically approved for the treatment of several cancers. Therapies targeting VEGF can modulate the tumor vasculature and the immune response. In this review, we discuss the roles of VEGF in the anti-tumor immune response. In addition, we summarize therapeutic strategies based on its inhibition, and their clinical approval.
Immunological aspects of cancer chemotherapy Kroemer, Guido; Apetoh, Lionel; Ghiringhelli, François ...
Nature reviews. Immunology,
200801, 2008-Jan, 2008-1-00, 20080101, Letnik:
8, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Accumulating evidence indicates that the innate and adaptive immune systems make a crucial contribution to the antitumour effects of conventional chemotherapy-based and radiotherapy-based cancer ...treatments. Moreover, the molecular and cellular bases of the immunogenicity of cell death that is induced by cytotoxic agents are being progressively unravelled, challenging the guidelines that currently govern the development of anticancer drugs. Here, we review the immunological aspects of conventional cancer treatments and propose that future successes in the fight against cancer will rely on the development and clinical application of combined chemo- and immunotherapies.
The accumulation of regulatory T cells (Tregs) at high density in various human carcinomas is generally associated with a poor prognosis, as expected from their capacity to inhibit antitumor ...immunity. Surprisingly, in patients bearing colorectal carcinoma (CRC), high regulatory T-cell infiltration is associated with a favorable prognosis, as shown by the analysis of seven clinical studies. To explain this paradox, we emphasize a putative role of the dense microbiological flora present in the large intestine with a trend toward translocation through the tumor. This microbiological hazard requires a T-cell-mediated inflammatory anti-microbial response that involves Th17 cells and can thereby promote cancer growth. This Th17-cell-dependent proinflammatory and tumor-enhancing response can be attenuated by Tregs, thus constituting a possible explanation for their favorable role in CRC prognosis. The link between a high density of FOXP3-positive cells in CRC immune infiltrates and favorable prognosis should lead us to consider tumor infiltrating Tregs as allies to be respected, rather than enemies to be destroyed during trials of CRC treatment.
PDF
