Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance

Meyer, Melissa A.; Baer, John M.; Knolhoff, Brett L.; Nywening, Timothy M.; Panni, Roheena Z.; Su, Xinming; Weilbaecher, Katherine N.; Hawkins, William G.; Ma, Cynthia; Fields, Ryan C.; Linehan, David C.; Challen, Grant A.; Faccio, Roberta; Aft, Rebecca; DeNardo, David G.

doi:10.1038/s41467-018-03600-6

Cited by 160 publications

(133 citation statements)

References 68 publications

(127 reference statements)

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“…Our data support these previous studies, showing not only a link between CD103 + DC and CD8 + T cell infiltration but also increased Cxcl9 and Il-12b mRNA in tumors derived from Ccr2 −/− cancer cells. Altogether, these data support previous work showing that the regulation of CD103 + DC infiltration is a critical step in tumor immune surveillance (Broz et al, 2014;Meyer et al, 2018;Roberts et al, 2016). (D) Tumor growth is increased in Batf3 −/− hosts transplanted with Ccr2 −/− cancer cells, as determined by weekly caliper measurements (n = 9 in Ccr2 +/+ to Batf3 −/− hosts group, and n = 10 for the other three groups).…”

Section: Discussionsupporting

confidence: 91%

Cancer cell CCR2 orchestrates suppression of the adaptive immune response

Fein

Almeida

et al. 2020

Journal of Experimental Medicine

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C-C chemokine receptor type 2 (CCR2) is expressed on monocytes and facilitates their recruitment to tumors. Though breast cancer cells also express CCR2, its functions in these cells are unclear. We found that Ccr2 deletion in cancer cells led to reduced tumor growth and approximately twofold longer survival in an orthotopic, isograft breast cancer mouse model. Deletion of Ccr2 in cancer cells resulted in multiple alterations associated with better immune control: increased infiltration and activation of cytotoxic T lymphocytes (CTLs) and CD103+ cross-presenting dendritic cells (DCs), as well as up-regulation of MHC class I and down-regulation of checkpoint regulator PD-L1 on the cancer cells. Pharmacological or genetic targeting of CCR2 increased cancer cell sensitivity to CTLs and enabled the cancer cells to induce DC maturation toward the CD103+ subtype. Consistently, Ccr2−/− cancer cells did not induce immune suppression in Batf3−/− mice lacking CD103+ DCs. Our results establish that CCR2 signaling in cancer cells can orchestrate suppression of the immune response.

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Section: Discussionsupporting

confidence: 91%

Cancer cell CCR2 orchestrates suppression of the adaptive immune response

Fein

Almeida

et al. 2020

Journal of Experimental Medicine

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“…Previously, others have shown that breast tumors suppress cDC1 development from DC progenitors, resulting in decreased cDC1 abundance and reduced CD8 + T cell-mediated anti-tumor immunity [36]. The inhibition of cDC1 development by breast cancers is due to their production of G-CSF, a STAT3-activating cytokine [36]; consistent with these prior studies, we found PyMT tumor cells secrete G-CSF in culture. Our CD103 + cDC1 vaccination approach, therefore, allowed us to circumvent the inhibitory effects of PyMT-derived G-CSF on cDC1 development.…”

Section: Discussionsupporting

confidence: 89%

STAT3 Inhibits CD103+ cDC1 Vaccine Efficacy in Murine Breast Cancer

Chrisikos

Zhou

et al. 2020

Cancers

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Conventional dendritic cells (cDCs) are a critical immune population, composed of multiple subsets, and responsible for controlling adaptive immunity and tolerance. Although migratory type 1 cDCs (CD103+ cDC1s in mice) are necessary to mount CD8+ T cell-mediated anti-tumor immunity, whether and how tumors modulate CD103+ cDC1 function remain understudied. Signal Transducer and Activator of Transcription 3 (STAT3) mediates the intracellular signaling of tumor-associated immunosuppressive cytokines, such as interleukin (IL)-10; thus, we hypothesized that STAT3 restrained anti-tumor immune responses elicited by CD103+ cDC1s. Herein, we show that in vitro-derived STAT3-deficient (Stat3∆/∆) CD103+ cDC1s are refractory to the inhibitory effects of IL-10 on Toll-like receptor 3 (TLR3) agonist-induced maturation responses. In a tumor vaccination approach, we found Stat3∆/∆ CD103+ cDC1s restrained mammary gland tumor growth and increased mouse survival more effectively than STAT3-sufficient CD103+ cDC1s. In addition, vaccination with Stat3∆/∆ CD103+ cDC1s elicited increased amounts of tumor antigen-specific CD8+ T cells and IFN-γ+ CD4+ T cells in tumors and tumor-draining lymph nodes versus phosphate-buffered saline (PBS)-treated animals. Furthermore, IL-10 receptor-deficient CD103+ cDC1s controlled tumor growth to a similar degree as Stat3∆/∆ CD103+ cDC1s. Taken together, our data reveal an inhibitory role for STAT3 in CD103+ cDC1 maturation and regulation of anti-tumor immunity. Our results also suggest IL-10 is a key factor eliciting immunosuppressive STAT3 signaling in CD103+ cDC1s in breast cancer. Thus, inhibition of STAT3 in cDC1s may provide an important strategy to improve their efficacy in tumor vaccination approaches and cDC1-mediated control of anti-tumor immunity.

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“…Neutralizing antibodies were used to neutralize specific proteins. Specifically, mouse MIP‐2 antibody (MAB452, R&D); mouse MDC antibody (AF439, R&D); mouse RANTES antibody (AF478‐SP, R&D); and mouse G‐CSF (MAB414, R&D) were injected through intraperitoneal injection 2 hours prior to MPLA administration, and the dosage of antibodies refers to previous reports …”

Section: Methodsmentioning

confidence: 99%

Monophosphoryl lipid A alleviated radiation‐induced testicular injury through TLR4‐dependent exosomes

Zhe

Cao

Liao

et al. 2020

J Cellular Molecular Medi

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Radiation protection on male testis is an important task for ionizing radiation‐related workers or people who receive radiotherapy for tumours near the testicle. In recent years, Toll‐like receptors (TLRs), especially TLR4, have been widely studied as a radiation protection target. In this study, we detected that a low‐toxicity TLR4 agonist monophosphoryl lipid A (MPLA) produced obvious radiation protection effects on mice testis. We found that MPLA effectively alleviated testis structure damage and cell apoptosis induced by ionizing radiation (IR). However, as the expression abundance differs a lot in distinct cells and tissues, MPLA seemed not to directly activate TLR4 singling pathway in mice testis. Here, we demonstrated a brand new mechanism for MPLA producing radiation protection effects on testis. We observed a significant activation of TLR4 pathway in macrophages after MPLA stimulation and identified significant changes in macrophage‐derived exosomes protein expression. We proved that after MPLA treatment, macrophage‐derived exosomes played an important role in testis radiation protection, and specially, G‐CSF and MIP‐2 in exosomes are the core molecules in this protection effect.

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Breast and pancreatic cancer interrupt IRF8-dependent dendritic cell development to overcome immune surveillance

Cited by 160 publications

References 68 publications

Cancer cell CCR2 orchestrates suppression of the adaptive immune response

Cancer cell CCR2 orchestrates suppression of the adaptive immune response

STAT3 Inhibits CD103+ cDC1 Vaccine Efficacy in Murine Breast Cancer

Monophosphoryl lipid A alleviated radiation‐induced testicular injury through TLR4‐dependent exosomes

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