Impaired immunity in patients with late-stage cancer is not limited to antitumor responses, as demonstrated by poor vaccination protection and high susceptibility to infection1,2,3. This has been largely attributed to chemotherapy-induced impairment of innate immunity, such as neutropenia2, whereas systemic effects of tumors on hematopoiesis and adoptive immunity remain incompletely understood. Here we observed anemia associated with severe deficiency of CD8+ T cell responses against pathogens in treatment-naive mice bearing large tumors. Specifically, we identify CD45+ erythroid progenitor cells (CD71+TER119+; EPCs) as robust immunosuppressors. CD45+ EPCs, induced by tumor growth–associated extramedullary hematopoiesis, accumulate in the spleen to become a major population, outnumbering regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs). The CD45+ EPC transcriptome closely resembles that of MDSCs, and, like MDSCs, reactive oxygen species production is a major mechanism underlying CD45+ EPC–mediated immunosuppression. Similarly, an immunosuppressive CD45+ EPC population was detected in patients with cancer who have anemia. These findings identify a major population of immunosuppressive cells that likely contributes to the impaired T cell responses commonly observed in patients with advanced cancer.
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
All original data used in this study are available upon request. All published noncommercial reagents can be made available upon request. The RNA-seq data are available through GEO repository (GSE106384).
Baden, L. R. et al. Prevention and treatment of cancer-related infections. J. Natl. Compr. Canc. Netw. 10, 1412–1445 (2012).
Vento, S., Cainelli, F. & Temesgen, Z. Lung infections after cancer chemotherapy. Lancet. Oncol. 9, 982–992 (2008).
van der Burg, S. H., Arens, R., Ossendorp, F., van Hall, T. & Melief, C. J. Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat. Rev. Cancer 16, 219–233 (2016).
Bodey, G. P. Infection in cancer patients. A continuing association. Am. J. Med. 81, 11–26 (1986).
Kosmidis, C. I. & Chandrasekar, P. H. Management of gram-positive bacterial infections in patients with cancer. Leuk. Lymphoma 53, 8–18 (2012).
Segal, B. H. et al. Prevention and treatment of cancer-related infections. J. Natl. Compr. Canc. Netw. 6, 122–174 (2008).
Ugel, S. et al. Immune tolerance to tumor antigens occurs in a specialized environment of the spleen. Cell Reports 2, 628–639 (2012).
Cortez-Retamozo, V. et al. Origins of tumor-associated macrophages and neutrophils. Proc. Natl. Acad. Sci. USA 109, 2491–2496 (2012).
Elahi, S. et al. Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature 504, 158 (2013).
Bennett, M., Pinkerton, P. H., Cudkowicz, G. & Bannerman, R. M. Hemopoietic progenitor cells in marrow and spleen of mice with hereditary iron deficiency anemia. Blood 32, 908–921 (1968).
Nakada, D. et al. Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy. Nature 505, 555 (2014).
Baldridge, M. T., King, K. Y., Boles, N. C., Weksberg, D. C. & Goodell, M. A. Quiescent haematopoietic stem cells are activated by IFN-γ in response to chronic infection. Nature 465, 793–797 (2010).
Inra, C. N. et al. A perisinusoidal niche for extramedullary haematopoiesis in the spleen. Nature 527, 466 (2015).
Freedman, M. H. & Saunders, E. F. Hematopoiesis in the human spleen. Am. J. Hematol. 11, 271–275 (1981).
Lowell, C. A., Niwa, M., Soriano, P. & Varmus, H. E. Deficiency of the Hck and Src tyrosine kinases results in extreme levels of extramedullary hematopoiesis. Blood 87, 1780–1792 (1996).
Cheshier, S. H., Prohaska, S. S. & Weissman, I. L. The effect of bleeding on hematopoietic stem cell cycling and self-renewal. Stem. Cells. Dev. 16, 707–717 (2007).
Craig, W., Poppema, S., Little, M. T., Dragowska, W. & Lansdorp, P. M. CD45 isoform expression on human haemopoietic cells at different stages of development. Br. J. Haematol. 88, 24–30 (1994).
Harashima, A. et al. CD45 tyrosine phosphatase inhibits erythroid differentiation of umbilical cord blood CD34+ cells associated with selective inactivation of Lyn. Blood 100, 4440–4445 (2002).
Chen, K. et al. Resolving the distinct stages in erythroid differentiation based on dynamic changes in membrane protein expression during erythropoiesis. Proc. Natl. Acad. Sci. USA 106, 17413–17418 (2009).
Guy, C. T., Cardiff, R. D. & Muller, W. J. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol. Cell. Biol. 12, 954–961 (1992).
Gabrilovich, D. I. & Nagaraj, S. Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162–174 (2009).
Kusmartsev, S., Nefedova, Y., Yoder, D. & Gabrilovich, D. I. Antigen-specific inhibition of CD8+ T cell response by immature myeloid cells in cancer is mediated by reactive oxygen species. J. Immunol. 172, 989–999 (2004).
Lam, G. Y., Huang, J. & Brumell, J. H. The many roles of NOX2 NADPH oxidase–derived ROS in immunity. Semin. Immunopathol. 32, 415–430 (2010).
Sareila, O., Kelkka, T., Pizzolla, A., Hultqvist, M. & Holmdahl, R. NOX2 complex–derived ROS as immune regulators. Antioxid. Redox. Signal. 15, 2197–2208 (2011).
Devadas, S., Zaritskaya, L., Rhee, S. G., Oberley, L. & Williams, M. S. Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: selective regulation of mitogen-activated protein kinase activation and fas ligand expression. J. Exp. Med. 195, 59–70 (2002).
Zhang, B. et al. MicroRNA-23a curbs necrosis during early T cell activation by enforcing intracellular reactive oxygen species equilibrium. Immunity 44, 568–581 (2016).
Jackson, S. H., Devadas, S., Kwon, J., Pinto, L. A. & Williams, M. S. T cells express a phagocyte-type NADPH oxidase that is activated after T cell receptor stimulation. Nat. Immunol. 5, 818–827 (2004).
Khanna, R. & Burrows, S. R. Role of cytotoxic T lymphocytes in Epstein–Barr virus–associated diseases. Annu. Rev. Microbiol. 54, 19–48 (2000).
Hislop, A. D., Taylor, G. S., Sauce, D. & Rickinson, A. B. Cellular responses to viral infection in humans: lessons from Epstein–Barr virus. Annu. Rev. Immunol. 25, 587–617 (2007).
Han, Y. et al. Tumor-induced generation of splenic erythroblast-like Ter-cells promotes tumor progression. Cell 173, 634–648 (2018).
MMTV-PyMT mice were kindly provided by X. Liu (State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai). P14 (CD90.1) TCR transgenic mice were obtained from R. Ahmed at Emory University. Q.-J.L. is a Whitehead Family Foundation Scholar and supported by the National Institute of Allergy and Infectious Disease (NIAID; R01-AI091878), the National Cancer Institute (NCI; P50-CA190991), and the National Institutes of Health (NIH) Beau Biden Cancer Moonshot Initiative (R33CA225328). This work is also supported by the National Nature Science Foundation of China (grant nos. 81472648, 81500089, 81620108023, 81222031, 81773041 and 31600733), by the Research on The Basis and Frontier of Chongqing (grant nos. cstc2016jcyjA0049).
The authors declare no competing interests.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Zhao, L., He, R., Long, H. et al. Late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells. Nat Med 24, 1536–1544 (2018). https://doi.org/10.1038/s41591-018-0205-5
Breast cancer induces systemic immune changes on cytokine signaling in peripheral blood monocytes and lymphocytes
Journal of Leukocyte Biology (2020)
Cellular and Molecular Life Sciences (2020)
Cellular & Molecular Immunology (2020)
JCI Insight (2019)