Tumor-derived granulocyte-macrophage colony stimulating factor regulates myeloid inflammation and T cell immunity in pancreatic cancer

By L. Bayne, G. Beatty, N. Jhala, Carolyn E. Clark, A. Rhim, B. Stanger, R. Vonderheide. Cancer Cell, 2012

901 citations recorded by the source corpus.

Summary Cancer-associated inflammation is thought to be a barrier to immune surveillance, particularly in pancreatic ductal adenocarcinoma (PDA). Gr-1+ CD11b+ cells are a key feature of cancer inflammation in PDA, but remain poorly understood. Using a genetically engineered mouse model of PDA, we show that tumor-derived GM-CSF is necessary and sufficient to drive the development of Gr-1+ CD11b+ cells that suppressed antigen-specific T cells. In vivo, abrogation of tumor-derived GM-CSF inhibited the recruitment of Gr-1+ CD11b+ cells to the tumor microenvironment and blocked tumor development - a finding that was dependent on CD8+ T cells. In humans, PDA tumor cells prominently expressed GM-CSF in vivo. Thus, tumor-derived GM-CSF is an important regulator of inflammation and immune suppression within the tumor microenvironment.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/7723db0f1ad1edd2abde4ef001c6d0efabb4e79a

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In Immunology

1. Lisa M. Coussens
2. A. Sica
3. F. Balkwill
4. A. Mantovani
5. D. DeNardo
6. V. Bronte
7. A. Wang-Gillam
8. Scott W. Lowe

In Oncology

1. A. Sica
2. Lisa M. Coussens
3. F. Balkwill
4. A. Mantovani
5. D. DeNardo
6. V. Bronte
7. M. Pittet
8. Scott W. Lowe

Citations in the corpus

• CSF1/CSF1R Blockade Reprograms Tumor-Infiltrating Macrophages and Improves Response to T Cell Checkpoint Immunotherapy in Pancreatic Cancer Models (2014, positive): “For example, in response to lipopolysaccharide, CSF2-derived macrophages preferentially produce IL6, IL12, and TNFa, whereas CSF1-derived macrophages produce IL10 and CCL-2, but not IL12.”
• Low-dose irradiation programs macrophage differentiation to an iNOS⁺/M1 phenotype that orchestrates effective T cell immunotherapy. (2013, background): “VEGF is a key factor driving the formation of the typically aberrant tumor vasculature and thereby endothelial anergy (Motz and Coukos, 2011), while GM-CSF is an important mediator in the recruitment and maintenance of myeloid suppressor cells in tumor tissues (Bayne et al., 2012).”
• CXCR2 Inhibition Profoundly Suppresses Metastases and Augments Immunotherapy in Pancreatic Ductal Adenocarcinoma (2016, positive): “Recent studies have described the contribution of MDSCs to pancreatic cancer progression (Bayne et al., 2012), and the accumulation of MDSCs in patients with advanced pancreatic cancer correlates with disease stage (Diaz-Montero et al., 2009).”
• Targeting tumor-associated macrophages with anti-CSF-1R antibody reveals a strategy for cancer therapy. (2014, background): “In particular, pancreatic can- cer has been described to express GM-CSF, and the role of this growth factor in inducing immunosuppressive myeloid-derived suppressor cells in mouse models has been reported (Bayne et al., 2012; Dolcetti et al., 2010; Bronte et al., 2000).”
• The spleen in local and systemic regulation of immunity (2013, background): “Splenic pDCs are conditioned by soluble factors (like TGF-b) released from macrophages processing apoptotic material and contribute to antigen tolerance, e.g., in the context of allogeneic bone marrow transplantation (Bonnefoy et al., 2011).”