Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor

Nishio, Hiroshi; Yaguchi, Tomonori; Sugiyama, Juri; Sumimoto, Hidetoshi; Umezawa, Kazuo; Iwata, Takashi; Susumu, Nobuyuki; Fujii, Takeshi; Kawamura, Naoshi; Kobayashi, Asuka; Park, J; Aoki, Daisuke; Kawakami, Yutaka

doi:10.1038/bjc.2014.251

Cited by 60 publications

(52 citation statements)

References 42 publications

(53 reference statements)

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“…However, our results certainly confirm previous findings: decrease of IL-10 after cytoreduction 16 and an increase of IL-10, TGF-b and arginase in ovarian cancer patients at diagnosis. 17,18 In contrast to reported findings on VEGF, we could not correlate the presence of VEGF to prognosis nor did we see an increase after surgery. [19][20][21][22][23] We found that gal-1 serum levels increased after three cycles of paclitaxel-carboplatin.…”

Section: Discussioncontrasting

confidence: 99%

“…Table 1 Arginase-1 MDSC are a heterogeneous group of cells that act immune suppressive and tumor promoting through secretion of inflammatory mediators, such as ROS and NO, IDO and arginase. 8 Arginase-1 causes depletion of L-arginine, which results in T cell anergy 40 Also TAM produce arginase-1 [41][42][43] Increased plasma arginase has been observed in EOC patients 18 …”

Section: Introductionmentioning

confidence: 99%

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Immunosuppressive parameters in serum of ovarian cancer patients change during the disease course

et al. 2015

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Neoplastic cells can escape immune control leading to cancer growth. Regulatory T cells (Treg), myeloidderived suppressor cells (MDSC) and tumor-associated macrophages (TAM) are crucial in immune escape. TAM are divided based on their immune profile, M1 are immunostimulatory while M2 are immunosuppressive. Research so far has mainly focused on the intratumoral behavior of these cells. This study, on the other hand, explored the systemic changes of the key metabolites [IL-4 (interleukin), IL-13, arginase, IL-10, VEGF-A (vascular endothelial growth factor), CCL-2 (chemokine (C-C) motif ligand 2) and TGF-b (transforming growth factor)] linked to Treg, MDSC and TAM during the course of the disease in ovarian and fallopian tube cancer patients. Serum samples were therefore analyzed at diagnosis, after (interval)-debulking surgery and after chemotherapy (paclitaxel-carboplatin). We also determined galectin-1 (gal-1), involved in angiogenesis and tumor-mediated immune evasion. We found significantly lower levels of IL-10, VEGF-A, TGF-b and arginase and higher levels of gal-1 after chemotherapy compared to diagnosis. After debulking surgery, a decrease in IL-10 was significant. Gal-1 and CCL-2 appeared independent prognostic factors for progression-free and overall survival (OS) (multivariate analysis). These results will help us in the decision making of future therapies in order to further modulate the immune system in a positive way.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immunosuppressive parameters in serum of ovarian cancer patients change during the disease course

et al. 2015

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“…One strategy to reduce the effects of these immunosuppressive cancer stromal cells is to use neutralizing antibodies or inhibitors of immunosuppressive effector molecules produced by the stromal cells. We and other groups previously reported that targeting signaling pathways such as STAT3 or NF‐κB in cancer‐associated immunosuppressive cells could augment anti‐tumor T‐cell immune responses by reducing cancer‐associated immunosuppression . Several studies have shown that currently used molecular target drugs for these pathways have synergistic anti‐tumor effects when combined with immunotherapies through immune‐related mechanisms …”

Section: Introductionmentioning

confidence: 99%

Involvement of local renin‐angiotensin system in immunosuppression of tumor microenvironment

et al. 2017

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To improve current cancer immunotherapies, strategies to modulate various immunosuppressive cells including myeloid derived suppressor cells (MDSC) which were shown to be negative factors in immune‐checkpoint blockade therapy, need to be developed. In the present study, we evaluated the role of the local renin‐angiotensin system (RAS) in the tumor immune‐microenvironment using murine models bearing tumor cell lines in which RAS was not involved in their proliferation and angiogenetic ability. Giving angiotensin II receptor blockers (ARB) to C57BL/6 mice bearing murine colon cancer cell line MC38 resulted in significant enhancement of tumor antigen gp70 specific T cells. ARB administration did not change the numbers of CD11b+ myeloid cells in tumors, but significantly reduced their T‐cell inhibitory ability along with decreased production of various immunosuppressive factors including interleukin (IL)‐6, IL‐10, vascular endothelial growth factor (VEGF), and arginase by CD11b+ cells in tumors. ARB also decreased expression of immunosuppressive factors such as chemokine ligand 12 and nitric oxide synthase 2 in cancer‐associated fibroblasts (CAF). Last, combination of ARB and anti‐programmed death‐ligand 1 (PD‐L1) antibodies resulted in significant augmentation of anti‐tumor effects in a CD8+ T cell‐dependent way. These results showed that RAS is involved in the generation of an immunosuppressive tumor microenvironment caused by myeloid cells and fibroblasts, other than the previously shown proliferative and angiogenetic properties of cancer cells and macrophages, and that ARB can transform the immunosuppressive properties of MDSC and CAF and could be used in combination with PD‐1/PD‐L1 immune‐checkpoint blockade therapy.

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“…Two types of immunosuppression mechanisms operate in the TME 53,54) . One is tumor- Wnt-β-catenin signaling pathway 55,56) , the MAPK signaling pathway 57,58) , the JAK-STAT3 signaling pathway 57,59) , and the NF-κB signaling pathway 60) . .…”

Section: Immunosuppressive Tme and Act Therapiesmentioning

confidence: 99%

Prospects for personalized combination immunotherapy for solid tumors based on adoptive cell therapies and immune checkpoint blockade therapies

Kato

Yaguchi

Iwata

et al. 2017

Jpn. J. Clin. Immunol.

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summaryImmune checkpoint blockade (ICB) and adoptive cell therapies (ACT) with antigen-receptor gene-engineered T cells have been shown to be successful for a limited number of patients with solid tumors. Responders to ICB therapy typically have T cell-inflamed tumors. Thus, it is important to develop strategies that convert non-T cell-inflamed tumors to T cell-inflamed tumors. Although chimeric antigen receptor transduced T (CAR-T) cell therapy targeting hematological malignancies demonstrated durable clinical responses, the success of gene-engineered T cell therapies in solid tumors is hampered by a lack of unique antigens, antigen loss in cancer cells, and the immune-suppressive tumor microenvironment (TME) of solid tumors. However, gene-engineered T cells possess strong killing activity and cytokine production capacity, which can induce antigen spreading and modulate the TME of non-T cell-inflamed tumors seen in non-responders to ICB therapy. Immune responses against cancer are highly heterogeneous, not only between tumor types, but also within a patient or between different patients with the same type of cancer, indicating that personalized immunotherapy should be employed, based on the immune status of the individual patient. Here, we offer our perspective for personalized combination immunotherapy for solid tumors based on ACT and ICB therapies.

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Immunosuppression through constitutively activated NF-κB signalling in human ovarian cancer and its reversal by an NF-κB inhibitor

Cited by 60 publications

References 42 publications

Immunosuppressive parameters in serum of ovarian cancer patients change during the disease course

Immunosuppressive parameters in serum of ovarian cancer patients change during the disease course

Involvement of local renin‐angiotensin system in immunosuppression of tumor microenvironment

Prospects for personalized combination immunotherapy for solid tumors based on adoptive cell therapies and immune checkpoint blockade therapies

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