Macrophage Expression of HIF-1α Suppresses T cell Function and Promotes Tumor Progression

By A. Doedens, C. Stockmann, M. Rubinstein, D. Liao, Na Zhang, D. DeNardo, Lisa M. Coussens, M. Karin, Ananda W. Goldrath, Richard J. Johnson. Cancer Research, 2010

619 citations recorded by the source corpus.

T cells can inhibit tumor growth, but their function in the tumor microenvironment is often suppressed. Many solid tumors exhibit abundant macrophage infiltration and low oxygen tension, yet how hypoxic conditions may affect innate immune cells and their impact on tumor progression is poorly understood. Targeted deletion of the hypoxia responsive transcription factor HIF-1α in macrophages in a progressive murine model of breast cancer resulted in reduced tumor growth, although VEGF-A and vascularization was unchanged. Tumor associated macrophages can suppress tumor infiltrating T cells by several mechanisms, and we found that hypoxia powerfully augmented macrophage-mediated T cell suppression in vitro in a manner dependent on macrophage expression of HIF-1α. Our findings link the innate immune hypoxic response to tumor progression through induction of T cell suppression in the tumor microenvironment.

Subfields: Cancer Research, Immunology, Physiology

View Paper: https://www.semanticscholar.org/paper/c01fc3f42cb8d9821f9800f61a9330730e38a5c3

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Lisa M. Coussens
2. D. Hanahan
3. J. Pollard
4. V. Nizet
5. V. Bronte
6. A. Palazón
7. Li Yang
8. Richard J. Johnson

In Immunology

1. Lisa M. Coussens
2. D. Hanahan
3. B. Ruffell
4. R. Noy
5. J. Pollard
6. D. DeNardo
7. V. Bronte
8. A. Mantovani

In Physiology

1. V. Bronte
2. Richard J. Johnson
3. J. Pollard
4. Lisa M. Coussens
5. D. Hanahan

Citations in the corpus

• Tumor-associated macrophages: from basic research to clinical application (2017, background): “Both of these factors can also regulate macrophage function [31].”
• PD-L1 is a novel direct target of HIF-1α, and its blockade under hypoxia enhanced MDSC-mediated T cell activation (2014, background): “, 2010), tumor-associated macrophages (TAMs; Doedens et al., 2010; Imtiyaz et al., 2010), and regulatory T cells (T reg cells; Clambey et al.”
• Macrophage Polarization in Inflammatory Diseases (2014, background): “The high expression of Arg1 in hypoxic zones is related to hypoxia-inducible factor (HIF)-1 and HIF-2, which regulate the suppressive capabilities of TAM and contribute to the TAM recruitment in models of inflammatory hepatocellular and colon carcinoma [78, 79] .”
• HIF Transcription Factors, Inflammation, and Immunity (2014, background): “Targeted deletion of HIF-1a in macrophages resulted in reduced tumor growth in a spontaneous PYMT mammary adenocarcinoma model, which was shown to result from improved lymphocyte proliferative capacity and function when myeloid HIF-1a is absent (Doedens et al., 2010; Lewis and Murdoch, 2005).”
• Leukocyte Complexity Predicts Breast Cancer Survival and Functionally Regulates Response to Chemotherapy (2011, background): “Malignant mammary epithelial cells from MMTV-PyMT mice express high levels of CSF1, which directly regulates TAM recruitment (and EGF expression) and induction of macrophage HIF1α (11, 38, 39).”
• Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells (2011, background): “Recently, hypoxia-inducible factor 1 was shown to drive the program leading to ARG1 and NOS2 up-regulation in mouse tumor-associated macrophages (Corzo et al., 2010; Doedens et al., 2010).”
• Accessories to the crime: functions of cells recruited to the tumor microenvironment. (2012, positive): “…by conventional tissue macrophages (Qian and Pollard, 2010), instead manifesting an ability to block CD8 + T cell proliferation or infiltration though release of factors with immunosuppressive potential (Denardo et al., 2011; Doedens et al., 2010; Kryczek et al., 2006; Movahedi et al., 2010).”