Lipid droplet (LD) accumulation is a now well-recognised hallmark of cancer. However, the significance of LD accumulation in colorectal cancer (CRC) biology is incompletely understood under ...chemotherapeutic conditions. Since drug resistance is a major obstacle to treatment success, we sought to determine the contribution of LD accumulation to chemotherapy resistance in CRC. Here we show that LD content of CRC cells positively correlates with the expression of lysophosphatidylcholine acyltransferase 2 (LPCAT2), an LD-localised enzyme supporting phosphatidylcholine synthesis. We also demonstrate that LD accumulation drives cell-death resistance to 5-fluorouracil and oxaliplatin treatments both in vitro and in vivo. Mechanistically, LD accumulation impairs caspase cascade activation and ER stress responses. Notably, droplet accumulation is associated with a reduction in immunogenic cell death and CD8
T cell infiltration in mouse tumour grafts and metastatic tumours of CRC patients. Collectively our findings highlight LPCAT2-mediated LD accumulation as a druggable mechanism to restore CRC cell sensitivity.
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.
Interferon regulatory factors (IRF) have critical functions in lymphoid development and in immune response regulation. Although many studies have described the function of IRF4 in CD4
T cells, few ...have focused on the IRF4 homologue, IRF8. Here, we show that IRF8 is required for Th9 differentiation in vitro and in vivo. IRF8 functions through a transcription factor complex consisting of IRF8, IRF4, PU.1 and BATF, which binds to DNA and boosts Il9 transcription. By contrast, IRF8 deficiency promotes the expression of other genes such as Il4, as IRF8 dimerises with the transcriptional repressor ETV6 and inhibits Il4 expression. In vivo, IRF8 is essential for the anti-tumour effects of Th9 cells in mouse melanoma models. Our results show that IRF8 complexes boost the Th9 program and repress Il4 expression to modulate Th9 cell differentiation, thereby implicating IRF8 as a potential therapeutic target to affect Th9 responses in cancer therapy.
CXCR3-CXCL9: It’s All in the Tumor Humblin, Etienne; Kamphorst, Alice O.
Immunity (Cambridge, Mass.),
06/2019, Letnik:
50, Številka:
6
Journal Article
Recenzirano
Odprti dostop
In this issue of Immunity, Chow et al. (2019) show that the CXCR3-CXCL9 axis is required for reinvigoration of intratumoral CD8+ T cell responses in response to PD-1 blockade and demonstrate that ...local guidance to dendritic cells, rather than recruitment of T cells into the tumor, underlies the importance of this chemokine axis.
In this issue of Immunity, Chow et al. (2019) show that the CXCR3-CXCL9 axis is required for reinvigoration of intratumoral CD8+ T cell responses in response to PD-1 blockade and demonstrate that local guidance to dendritic cells, rather than recruitment of T cells into the tumor, underlies the importance of this chemokine axis.
Chronic antigen stimulation leads to T cell exhaustion. Nutrient restrictions and other suppressive factors in the tumor microenvironment further exacerbate T cell dysfunction. Better understanding ...of heterogeneity and dynamics of exhausted CD8 T cells will guide novel therapies that modulate T cell differentiation to achieve more effective antitumor responses.
IL-9 was initially identified as a T cell growth factor with a potential oncogenic activity. Accordingly, IL-9 drives tumor growth in most hematological cancers. However, the links between IL-9 and ...cancer progression have been recently revisited following the discovery of T
H
9 cells. T
H
9 cells, which have been characterized in 2008 as a proinflammatory CD4 T cell subset that promotes protection against parasites and drives tissue inflammation in colitis, actually harbor potent IL-9-dependent anti-cancer properties in solid tumors and especially melanoma. While the molecular mechanisms underlying these observations are still being investigated, T
H
9 cells were demonstrated to activate both innate and adaptive immune responses, thereby favoring anti-cancer immunity and tumor elimination. Human T
H
9 cells have also been identified in cancer tissues, but their functions remain elusive. The present review aims to discuss the anti-cancer potential of T
H
9 cells and their possible clinical relevance for cancer immunotherapy.
Despite no apparent defects in T cell priming and recruitment to tumors, a large subset of T cell rich tumors fail to respond to immune checkpoint blockade (ICB). We leveraged a neoadjuvant anti-PD-1 ...trial in patients with hepatocellular carcinoma (HCC), as well as additional samples collected from patients treated off-label, to explore correlates of response to ICB within T cell-rich tumors. We show that ICB response correlated with the clonal expansion of intratumoral CXCL13
CH25H
IL-21
PD-1
CD4
T helper cells ("CXCL13
T
") and Granzyme K
PD-1
effector-like CD8
T cells, whereas terminally exhausted CD39
TOX
PD-1
CD8
T cells dominated in nonresponders. CD4
and CD8
T cell clones that expanded post-treatment were found in pretreatment biopsies. Notably, PD-1
TCF-1
(Progenitor-exhausted) CD8
T cells shared clones mainly with effector-like cells in responders or terminally exhausted cells in nonresponders, suggesting that local CD8
T cell differentiation occurs upon ICB. We found that these Progenitor CD8
T cells interact with CXCL13
T
within cellular triads around dendritic cells enriched in maturation and regulatory molecules, or "mregDC". These results suggest that discrete intratumoral niches that include mregDC and CXCL13
T
control the differentiation of tumor-specific Progenitor exhasuted CD8
T cells following ICB.
Abstract
During chronic infections and cancer, CD8 T cells that recognize pathogens/tumors can persist in a dysfunctional state characterized by high expression of the inhibitory receptor Programmed ...Cell Death (PD)-1. T cell factor (TCF)-1+PD-1+ progenitor exhausted cells (Tpex) maintain the antigen-specific T cell pool by self-renewal and differentiation into effector-like TCF-1negPD-1+CD8 T cells. Previous studies described that among PD-1+ CD8 T cells, only Tpex respond to PD-1 blockade therapy. However, the molecular mechanisms that support Tpex self-renewal or differentiation are not understood. Tpex have high CD28 expression and we demonstrated that CD28 costimulation is required for response to PD-1 targeted therapy. To better understand the role of CD28 on Tpex, we evaluated how reduction or abrogation of CD28 signaling impacted virus-specific CD8 T cells in mice infected with lymphocytic choriomeningitis virus (LCMV). During established chronic infection, deletion of both Cd28 alleles resulted in reduction of Tpex and TCF-1neg subsets. In contrast, when CD28 signaling was reduced (deletion of one allele), TCF-1negPD-1+ CD8 T cells decreased, but the number of Tpex was not affected. RNA sequencing and metabolic assays revealed that sustained CD28 signaling during persistent antigen stimulation is required to maintain mitochondrial fitness of Tpex. Our work supports the novel hypothesis that CD28 signaling strength modulates Tpex fate decision through metabolic regulation. Our data also suggest continuous CD28 signaling is required for long-term maintenance of antigen-specific PD-1+ CD8 T cells. These findings have important implications for checkpoint therapy in cancer.
Natural killer (NK) cells are commonly reduced in human tumors, enabling many to evade surveillance. Here, we sought to identify cues that alter NK cell activity in tumors. We found that, in human ...lung cancer, the presence of NK cells inversely correlated with that of monocyte-derived macrophages (mo-macs). In a murine model of lung adenocarcinoma, we show that engulfment of tumor debris by mo-macs triggers a pro-tumorigenic program governed by triggering receptor expressed on myeloid cells 2 (TREM2). Genetic deletion of Trem2 rescued NK cell accumulation and enabled an NK cell-mediated regression of lung tumors. TREM2
mo-macs reduced NK cell activity by modulating interleukin (IL)-18/IL-18BP decoy interactions and IL-15 production. Notably, TREM2 blockade synergized with an NK cell-activating agent to further inhibit tumor growth. Altogether, our findings identify a new axis, in which TREM2
mo-macs suppress NK cell accumulation and cytolytic activity. Dual targeting of macrophages and NK cells represents a new strategy to boost antitumor immunity.
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