Poly (I: C) modulates the immunosuppressive activity of myeloid-derived suppressor cells in a murine model of breast cancer

Forghani, Parvin; Waller, Edmund K.

doi:10.1007/s10549-015-3508-y

Cited by 38 publications

(28 citation statements)

References 37 publications

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“…52 Moreover, poly(I:C) abrogated the immunosuppressive functions of myeloid-derived suppressor cells in a murine breast cancer model, leading to an enhanced T cell influx and enhanced survival. 56 Recently, it has been shown that PD-1 on TAMs suppresses their phagocytic functions and antitumor immunity. 57 On the other hand, PD-1 ligand expression by TAMs may contribute to immunosuppression.…”

Section: Discussionmentioning

confidence: 99%

Poly(I:C) primes primary human glioblastoma cells for an immune response invigorated by PD-L1 blockade

et al. 2017

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Prognosis of glioblastoma remains dismal, underscoring the need for novel therapies. Immunotherapy is generating promising results, but requires combination strategies to unlock its full potential. We investigated the immunomodulatory capacities of poly(I:C) on primary human glioblastoma cells and its combinatorial potential with programmed death ligand (PD-L) blockade. In our experiments, poly(I:C) stimulated expression of both PD-L1 and PD-L2 on glioblastoma cells, and a pro-inflammatory secretome, including type I interferons (IFN) and chemokines CXCL9, CXCL10, CCL4 and CCL5. IFN-β was partially responsible for the elevated PD-1 ligand expression on these cells. Moreover, real-time PCR and chloroquine-mediated blocking experiments indicated that poly(I:C) triggered Toll-like receptor 3 to elicit its effect. Cocultures of poly(I:C)-treated glioblastoma cells with peripheral blood mononuclear cells enhanced lymphocytic activation (CD69, IFN-γ) and cytotoxic capacity (CD107a, granzyme B). Additional PD-L1 blockade further propagated immune activation. Besides activating immunity, poly(I:C)-treated glioblastoma cells also doubled the attraction of CD8 T cells, and to a lesser extent CD4 T cells, via a mechanism which included CXCR3 and CCR5 ligands. Our results indicate that by triggering glioblastoma cells, poly(I:C) primes the tumor microenvironment for an immune response. Secreted cytokines allow for immune activation while chemokines attract CD8 T cells to the front, which are postulated as a prerequisite for effective PD-1/PD-L1 blockade. Accordingly, additional blockade of the concurrently elevated tumoral PD-L1 further reinforces the immune activation. In conclusion, our data proposes poly(I:C) treatment combined with PD-L1 blockade to invigorate the immune checkpoint inhibition response in glioblastoma.

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Section: Discussionmentioning

confidence: 99%

Poly(I:C) primes primary human glioblastoma cells for an immune response invigorated by PD-L1 blockade

et al. 2017

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“…Several factors and agents targeting MDSCs have been investigated in recent years. Polyinosinic-polycytidylic acid, a ligand for TLR-3, decreases the number of MDSCs and the immunosuppressive activity in BC by augmenting the T cell response 131. In addition, previous studies have suggested that, in addition to its cytotoxicity against tumor cells, doxorubicin plays a major role in the reduction of MDSC-induced immunosuppression 132…”

Section: Tumor Microenvironmentmentioning

confidence: 99%

Mechanism of immune evasion in breast cancer

Wang¹,

Zhang²,

Song³

et al. 2017

OTT

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Breast cancer (BC) is the most common malignant tumor among women, with high morbidity and mortality. Its onset, development, metastasis, and prognosis vary among individuals due to the interactions between tumors and host immunity. Many diverse mechanisms have been associated with BC, with immune evasion being the most widely studied to date. Tumor cells can escape from the body’s immune response, which targets abnormal components and foreign bodies, using different approaches including modification of surface antigens and modulation of the surrounding environment. In this review, we summarize the mechanisms and factors that impact the immunoediting process and analyze their functions in detail.

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“…Pathogen-derived TLR agonists have been shown to induce accumulation of MDSC or to increase their activity 25 , 26 . Some studies, however, have demonstrated differentiation of mature myeloid cells promoting anti-tumor response upon treatment with TLR agonists 27 , 28 . Altogether, the impact of TLR agonists on anti-tumor response seems to be dependent on the cellular context 29 , 30 .…”

Section: Discussionmentioning

confidence: 99%

Genetic screen in myeloid cells identifies TNF-α autocrine secretion as a factor increasing MDSC suppressive activity via Nos2 up-regulation

Schröder

Krötschel

Conrad

et al. 2018

Sci Rep

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The suppressive microenvironment of tumors remains one of the limiting factors for immunotherapies. In tumors, the function of effector T cells can be inhibited by cancer cells as well as myeloid cells including tumor associated macrophages and myeloid-derived suppressor cells (MDSC). A better understanding of how myeloid cells inhibit T cell function will guide the design of therapeutic strategies to increase anti-tumor responses. We have previously reported the in vitro differentiation of MDSC from immortalized mouse hematopoietic progenitors and characterized the impact of retinoic acid and 3-deazaneplanocin A on MDSC development and function. We describe here the effect of these compounds on MDSC transcriptome and identify genes and pathway affected by the treatment. In order to accelerate the investigation of gene function in MDSC suppressive activity, we developed protocols for CRISPR/Cas9-mediated gene editing in MDSC. Through screening of 217 genes, we found that autocrine secretion of TNF-α contributes to MDSC immunosuppressive activity through up-regulation of Nos2. The approach described here affords the investigation of gene function in myeloid cells such as MDSC with unprecedented ease and throughput.

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Poly (I: C) modulates the immunosuppressive activity of myeloid-derived suppressor cells in a murine model of breast cancer

Cited by 38 publications

References 37 publications

Poly(I:C) primes primary human glioblastoma cells for an immune response invigorated by PD-L1 blockade

Poly(I:C) primes primary human glioblastoma cells for an immune response invigorated by PD-L1 blockade

Mechanism of immune evasion in breast cancer

Genetic screen in myeloid cells identifies TNF-α autocrine secretion as a factor increasing MDSC suppressive activity via Nos2 up-regulation

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