Dr. Bo Zhu’ group reveals that tumors hijack erythropoiesis for myelopoiesis and immunosuppression
Source：Bo Zhu
2022-06-16
As a “foreign organ”, tumor evolves mechanisms to evade immune rejection and gain immune tolerance and privilege. Dr. Bo Zhu’ group from Xinqiao Hospital of Army Medical University published a research article in Nature medicine in 2018, reported that late-stage tumors induce anemia and immunosuppressive extramedullary erythroid progenitor cells (EPCs). On May 19, 2022, Dr. Bo Zhu’ group published a follow up study titled “Tumor-Induced Erythroid Precursor-Differentiated Myeloid Cells Mediate Immunosuppression and Curtail Anti-PD-1/PD-L1 Treatment Efficacy” in Cancer cell. These studies reveal a feed-forward mechanism by which tumors exploit anemia-triggered erythropoiesis for myeloid trans-differentiation and immunosuppression to favor tumor immune evasion and curtail the efficacy of Immune checkpoint inhibitor (ICI) therapies.
Based on the 2018 study that tumor arrests the development of erythroid cells and to further assess the overall impact of tumorigenesis on erythroid development, Dr. Bo Zhu’ group collected bone marrow (BM) cells from bone metastasis-free cancer patient, and purified CD235a+ erythrocytes for scRNA-seq. Using Uniform Manifold Approximation and Projection, dimension reduction categorized BM erythrocytes into multiple clusters and one cluster surprisingly displays transcriptomic characteristic of myeloid cells. In vivo lineage tracking and single cell transcriptomic analyses validated that a significant portion of tumor-infiltrating myeloid cells are of erythroid origin. Further in vitro and in vivo experiments suggest that GM-CSF produced by tumor cells may mediate the initiation of CD45+ EPC trans-differentiation into the myeloid lineage. These cells are named Erythroid Precursor-Differentiated Myeloid Cell (EDMC). Together, this research suggests that, distinct from extramedullary hematopoiesis triggered by acute anemia, established tumors block the default red blood cell differentiation pathway of CD45+ EPCs and promote their differentiate into bona fide MDSC-like myeloid cells in the tumor.
Functionally, EDMC are immunosuppressive and express high levels of PD-L1, Arg-1, NOS2. and effective in suppressing CD8+ T cell proliferation, to accelerate tumor growth and shorten mouse survival. Clinically, the quantity of intra-tumoral EDMCs predicts T cell exhaustion and a tolerance microenvironment in majority of tumor types; and the enrichment of EDMC predicts resistance to ICI treatments in seven independent cohorts.
Since the EDMC is induced by anemia in cancer patients, researchers also observed that anemia is a hazard factor undermining the ICI efficacy in two independent cohorts. The new finding that arrested CD45+ EPCs can differentiate into EDMCs helps to explain the following clinical phenomena: while recombinant human erythropoietin (rhEPO) and erythropoiesis-stimulating agents (ESAs) promote red blood cell growth and can effectively treat anemia, they do not prolong the survival of cancer patients with anemia. These findings suggest that the poor efficacy of these drugs might be attributable to the hijacking of EPO/ESA-induced EPCs to produce EDMCs. In this scenario, it is urgent to study the mechanism(s) underlying the arrest of CD45+ EPC differentiation into red blood cells, which should support the development of corresponding drugs to overcome anemia while also diminishing EDMC generation.
In summary, here Dr. Bo Zhu’ group illustrated how an established tumor functions like a lymph organ to fundamentally alter hematopoiesis and immune responses in a manner that curtails the efficacy of ICI therapies. This process creates a feed-forward mechanism whereby sustained anemia repeatedly triggers extramedullary erythropoiesis, but tumor diverts extramedullary erythropoiesis from red blood cells to EDMCs to systemically suppress immune surveillance.
Professor Paulo C. Rodriguez from H. Lee Moffifitt Cancer Center published a review titled “Tumor-directed dysregulation of erythroid progenitors drives immunosuppressive myeloid cells” in Cancer cell of the same issue to comment on this research. This review pointed out that “Long et al. demonstrate that tumors can reprogram erythroid progenitors into myeloid-erythroid cells that promote immunosuppression. EDMCs expand in cancer-bearing individuals, resemble the functionality of myeloid-derived suppressor cells (MDSCs), and correlate with poor response to ICI and tumor-related anemia.”
Prof. Haixia long and Qingzhu Jia from Army Medical University, Prof. Liuyang Wang from Duke University are co-first authors. Prof. Bo Zhu from Army Medical University, Prof. Qi-Jing Li from Duke University are co-corresponding authors of this paper. Meanwhile, Prof. Xiao-Fan Wang, Yisong Y. Wan, Li Zhang, Caicun Zhou, Weiping Zou, and Limin Zheng contributed greatly to this work. This study was funded by the grants from National Nature Science foundation of China (Nos. 81472648, 81620108023, 82150119 and 81972699).
Links: https://doi.org/10.1016/j.ccell.2022.04.018
Based on the 2018 study that tumor arrests the development of erythroid cells and to further assess the overall impact of tumorigenesis on erythroid development, Dr. Bo Zhu’ group collected bone marrow (BM) cells from bone metastasis-free cancer patient, and purified CD235a+ erythrocytes for scRNA-seq. Using Uniform Manifold Approximation and Projection, dimension reduction categorized BM erythrocytes into multiple clusters and one cluster surprisingly displays transcriptomic characteristic of myeloid cells. In vivo lineage tracking and single cell transcriptomic analyses validated that a significant portion of tumor-infiltrating myeloid cells are of erythroid origin. Further in vitro and in vivo experiments suggest that GM-CSF produced by tumor cells may mediate the initiation of CD45+ EPC trans-differentiation into the myeloid lineage. These cells are named Erythroid Precursor-Differentiated Myeloid Cell (EDMC). Together, this research suggests that, distinct from extramedullary hematopoiesis triggered by acute anemia, established tumors block the default red blood cell differentiation pathway of CD45+ EPCs and promote their differentiate into bona fide MDSC-like myeloid cells in the tumor.
Functionally, EDMC are immunosuppressive and express high levels of PD-L1, Arg-1, NOS2. and effective in suppressing CD8+ T cell proliferation, to accelerate tumor growth and shorten mouse survival. Clinically, the quantity of intra-tumoral EDMCs predicts T cell exhaustion and a tolerance microenvironment in majority of tumor types; and the enrichment of EDMC predicts resistance to ICI treatments in seven independent cohorts.
Since the EDMC is induced by anemia in cancer patients, researchers also observed that anemia is a hazard factor undermining the ICI efficacy in two independent cohorts. The new finding that arrested CD45+ EPCs can differentiate into EDMCs helps to explain the following clinical phenomena: while recombinant human erythropoietin (rhEPO) and erythropoiesis-stimulating agents (ESAs) promote red blood cell growth and can effectively treat anemia, they do not prolong the survival of cancer patients with anemia. These findings suggest that the poor efficacy of these drugs might be attributable to the hijacking of EPO/ESA-induced EPCs to produce EDMCs. In this scenario, it is urgent to study the mechanism(s) underlying the arrest of CD45+ EPC differentiation into red blood cells, which should support the development of corresponding drugs to overcome anemia while also diminishing EDMC generation.
In summary, here Dr. Bo Zhu’ group illustrated how an established tumor functions like a lymph organ to fundamentally alter hematopoiesis and immune responses in a manner that curtails the efficacy of ICI therapies. This process creates a feed-forward mechanism whereby sustained anemia repeatedly triggers extramedullary erythropoiesis, but tumor diverts extramedullary erythropoiesis from red blood cells to EDMCs to systemically suppress immune surveillance.
Professor Paulo C. Rodriguez from H. Lee Moffifitt Cancer Center published a review titled “Tumor-directed dysregulation of erythroid progenitors drives immunosuppressive myeloid cells” in Cancer cell of the same issue to comment on this research. This review pointed out that “Long et al. demonstrate that tumors can reprogram erythroid progenitors into myeloid-erythroid cells that promote immunosuppression. EDMCs expand in cancer-bearing individuals, resemble the functionality of myeloid-derived suppressor cells (MDSCs), and correlate with poor response to ICI and tumor-related anemia.”
Summary by Professor Rodriguez's group
Prof. Haixia long and Qingzhu Jia from Army Medical University, Prof. Liuyang Wang from Duke University are co-first authors. Prof. Bo Zhu from Army Medical University, Prof. Qi-Jing Li from Duke University are co-corresponding authors of this paper. Meanwhile, Prof. Xiao-Fan Wang, Yisong Y. Wan, Li Zhang, Caicun Zhou, Weiping Zou, and Limin Zheng contributed greatly to this work. This study was funded by the grants from National Nature Science foundation of China (Nos. 81472648, 81620108023, 82150119 and 81972699).
Links: https://doi.org/10.1016/j.ccell.2022.04.018
