Primary Tumor Hypoxia Recruits CD11b+/Ly6Cmed/Ly6G+ Immune Suppressor Cells and Compromises NK Cell Cytotoxicity in the Premetastatic Niche

Sceneay, Jaclyn; Chow, Melvyn T.; Chen, Anna; Halse, Heloise M.; Wong, Christina S.F.; Andrews, Daniel M.; Sloan, Erica K.; Parker, Belinda S.; Bowtell, David D.L.; Smyth, Mark J.; Möller, Andreas

doi:10.1158/0008-5472.can-11-3873

Cited by 315 publications

(287 citation statements)

References 20 publications

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“…Since no changes in CLP were observed in the bone marrow ( Supplementary Fig. 8B), it is possible that these T cell changes are a consequence of the increased Gr1 þ cell numbers as the latter have been shown previously to have immune suppressive properties 23,24 . Metastasis and neutrophil recruitment are dependent on complex cytokine networks.…”

Section: Fak Deficiency Shifts Hscs Towards a Myeloid Commitmentmentioning

confidence: 80%

“…MDSCs are a mixture of myeloid cells with characteristics of monocytes and granulocytes and are generally described by the co-expression of the mouse markers CD11b and Gr1 (CD11b þ Gr1 þ ) 21,22 . Their expansion at metastatic sites generates an immunosuppressive niche that suppresses T cell activation, proliferation and cytotoxicity and also suppresses NK cell cytotoxicity [23][24][25][26] . These cells have been shown to facilitate tumour cell seeding and colonization at metastatic sites and are thereby thought to drive metastasis [27][28][29] .…”

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confidence: 99%

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Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis

et al. 2014

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Metastasis is the main cause of cancer-related death and thus understanding the molecular and cellular mechanisms underlying this process is critical. Here, our data demonstrate, contrary to established dogma, that loss of haematopoietic-derived focal adhesion kinase (FAK) is sufficient to enhance tumour metastasis. Using both experimental and spontaneous metastasis models, we show that genetic ablation of haematopoietic FAK does not affect primary tumour growth but enhances the incidence of metastasis significantly. At a molecular level, haematopoietic FAK deletion results in an increase in PU-1 levels and decrease in GATA-1 levels causing a shift of hematopoietic homeostasis towards a myeloid commitment. The subsequent increase in circulating granulocyte number, with an increase in serum CXCL12 and granulocyte CXCR4 levels, was required for augmented metastasis in mice lacking haematopoietic FAK. Overall our findings provide a mechanism by which haematopoietic FAK controls cancer metastasis.

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Section: Fak Deficiency Shifts Hscs Towards a Myeloid Commitmentmentioning

confidence: 80%

mentioning

confidence: 99%

Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis

et al. 2014

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“…Furthermore, Kowanetz et al [26] showed that depletion of Gr1 + or Ly6G + cells from the pre-metastatic lung results in reduced metastasis. Similarly, Sceneay et al [304] also observed increased numbers of granulocytic CD11b + Ly6C med Ly6G + myeloid cells in the pre-metastastic lungs in mice injected with melanoma or breast carcinoma cells with a concomitant reduction in the cytotoxic activity of NK cells [304]. Erler et al [305] observed that lysyl oxidase (LOX) secreted by hypoxic breast tumor cells is required for the recruitment of immature myeloid CD11b + F4/80 − cells to the premetastatic lung.…”

Section: Neutrophils In Pre-metastatic Organs -The "Seed and Soil" Hymentioning

confidence: 96%

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

Sionov

Fridlender

Granot

2014

Cancer Microenvironment

324

261

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Neutrophils are myeloid cells that constitute 50-70 % of all white blood cells in the human circulation. Traditionally, neutrophils are viewed as the first line of defense against infections and as a major component of the inflammatory process. In addition, accumulating evidence suggest that neutrophils may also play a key role in multiple aspects of cancer biology. The possible involvement of neutrophils in cancer prevention and promotion was already suggested more than half a century ago, however, despite being the major component of the immune system, their contribution has often been overshadowed by other immune components such as lymphocytes and macrophages. Neutrophils seem to have conflicting functions in cancer and can be classified into anti-tumor (N1) and pro-tumor (N2) sub-populations. The aim of this review is to discuss the varying nature of neutrophil function in the cancer microenvironment with a specific emphasis on the mechanisms that regulate neutrophil mobilization, recruitment and activation.

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“…As Ly6G1 granulocytic polymorphonuclear neutrophil subsets of myeloid-derived suppressor cells (PMN-MDSC) reportedly impair NK cell development specifically [38][39][40] and as cross-talk between tumor-associated macrophages and MDSCs has been shown to sustain and exacerbate immune suppression in the tumor microenvironment, 41 we tested whether this population was also involved in preventing NK cell expansion induced by CpG-ODN aerosol. Four groups of mice (5 mice/group) were injected with B16 cells as above and, 96 hr later, treated every 72-96 hr with the Ly6G-specific mAb (1A8), which recognizes and depletes Ly6Ghigh neutrophilic populations, or with isotype control.…”

Section: Anti-tumor Activity Of Aerosol Cpg-odn Treatment Against B16mentioning

confidence: 99%

Anti‐tumor activity of CpG‐ODN aerosol in mouse lung metastases

Sfondrini

Sommariva

Tortoreto

et al. 2013

Intl Journal of Cancer

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Studies in preclinical models have demonstrated the superior anti-tumor effect of CpG oligodeoxynucleotides (CpG-ODN) when administered at the tumor site rather than systemically. We evaluated the effect of aerosolized CpG-ODN on lung metastases in mice injected with immunogenic N202.1A mammary carcinoma cells or weakly immunogenic B16 melanoma cells. Upon reaching the bronchoalveolar space, aerosolized CpG-ODN activated a local immune response, as indicated by production of IL-12p40, IFN-c and IL-1b and by recruitment and maturation of DC cells in bronchoalveolar lavage fluid of mice. Treatment with aerosolized CpG-ODN induced an expansion of CD41 cells in lung and was more efficacious than systemic i.p. administration against experimental lung metastases of immunogenic N202.1A mammary carcinoma cells, whereas only i.p. delivery of CpG-ODN provided anti-tumor activity, which correlated with NK cell expansion in the lung, against lung metastases of the poorly immunogenic B16 melanoma. The inefficacy of aerosol therapy to induce NK expansion was related to the presence of immunosuppressive macrophages in B16 tumor-bearing lungs, as mice depleted of these cells by clodronate treatment responded to aerosol CpG-ODN through expansion of the NK cell population and significantly reduced numbers of lung metastases. Our results indicate that tumor immunogenicity and the tumor-induced immunosuppressive environment are critical factors to the success of CpG therapy in the lung, and point to the value of routine sampling of the lung immune environment in defining an optimal immunotherapeutic strategy.

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Primary Tumor Hypoxia Recruits CD11b+/Ly6Cmed/Ly6G+ Immune Suppressor Cells and Compromises NK Cell Cytotoxicity in the Premetastatic Niche

Cited by 315 publications

References 20 publications

Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis

Haematopoietic focal adhesion kinase deficiency alters haematopoietic homeostasis to drive tumour metastasis

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

Anti‐tumor activity of CpG‐ODN aerosol in mouse lung metastases

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