Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy

Long, Haixia; Jia, Qingzhu; Wang, Liuyang; Fang, Wenfeng; Wang, Zhongyu; Jiang, Tao; Zhou, Fei; Zheng, Jin; Huang, Jiani; Zhou, Li; Hu, Chunyan; Wang, Xinxin; Zhang, Jin; Ba, Yujie; Gong, Ye; Zeng, Xi; Zeng, Dong; Su, Xingxing; Alexander, Peter; Wang, Li; Wang, Limei; Wan, Yisong Y.; Wang, Xiaofan; Zhang, Li; Li, Qi-Jing; Zhu, Bo

doi:10.1016/j.ccell.2022.04.018

Cited by 76 publications

(63 citation statements)

References 101 publications

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“…Further work by the same team demonstrated a major restructuring of the hierarchical organization of erythropoiesis in patients with advanced cervical carcinoma and in mouse models, including the MMTV-PyMT transgenic model of spontaneous breast cancer and mice inoculated subcutaneously with LLC lung carcinoma, B16-F10 melanoma, or MC38 colon adenocarcinoma ( 143 ). Both patients and mouse models with advanced cancer harboured myeloid cells that co-expressed markers and transcriptional signatures of the erythroid cell lineage ( 143 ). Furthermore, EPCs in these models, but not in the corresponding healthy controls, had a significant potential for myeloid differentiation, and this was further enhanced with GM-CSF exposure or transplantation into tumor bearing mice.…”

Section: Erythropoiesis Dysfunction Contributes To Cancer Immunosuppr...mentioning

confidence: 99%

“…Furthermore, when administered to mice EDMCs promoted melanoma metastasis and resistance to immune checkpoint inhibitor (ICI) therapy. Importantly, EDMC transcriptional signatures in human cancers also correlated with CD8 T cell exhaustion, other markers of cancer immune evasion, and with an impaired response to ICI therapy ( 143 ).…”

Section: Erythropoiesis Dysfunction Contributes To Cancer Immunosuppr...mentioning

confidence: 99%

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Hematologic dysfunction in cancer: Mechanisms, effects on antitumor immunity, and roles in disease progression

2022

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With the major advances in cancer immunology and immunotherapy, it is critical to consider that most immune cells are short-lived and need to be continuously replenished from hematopoietic stem and progenitor cells. Hematologic abnormalities are prevalent in cancer patients, and many ground-breaking studies over the past decade provide insights into their underlying cellular and molecular mechanisms. Such studies demonstrate that the dysfunction of hematopoiesis is more than a side-effect of cancer pathology, but an important systemic feature of cancer disease. Here we review these many advances, covering the cancer-associated phenotypes of hematopoietic stem and progenitor cells, the dysfunction of myelopoiesis and erythropoiesis, the importance of extramedullary hematopoiesis in cancer disease, and the developmental origins of tumor associated macrophages. We address the roles of many secreted mediators, signaling pathways, and transcriptional and epigenetic mechanisms that mediate such hematopoietic dysfunction. Furthermore, we discuss the important contribution of the hematopoietic dysfunction to cancer immunosuppression, the possible avenues for therapeutic intervention, and highlight the unanswered questions and directions for future work. Overall, hematopoietic dysfunction is established as an active component of the cancer disease mechanisms and an important target for therapeutic intervention.

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Section: Erythropoiesis Dysfunction Contributes To Cancer Immunosuppr...mentioning

confidence: 99%

Section: Erythropoiesis Dysfunction Contributes To Cancer Immunosuppr...mentioning

confidence: 99%

Hematologic dysfunction in cancer: Mechanisms, effects on antitumor immunity, and roles in disease progression

2022

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“…Tumours support the emergency myelopoiesis favouring the generation of unconventional mature and immature myeloid cells endowed with tumour-promoting activities [ 20 , 21 ]. For instance, a significant portion of tumour-infiltrating myeloid cells are of erythroid origin [ 22 ], highlighting how tumour reprograms myeloid cell differentiation. In this scenario, TAMs and MDSCs represent the ultimate commitment of the tumour-dependent myeloid-cell reprogramming [ 23 , 24 ] and will be the focus of this review.…”

Section: Myeloid Cells In Tumour Microenvironmentmentioning

confidence: 99%

Targeting tumour-reprogrammed myeloid cells: the new battleground in cancer immunotherapy

et al. 2022

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Tumour microenvironment is a complex ecosystem in which myeloid cells are the most abundant immune elements. This cell compartment is composed by different cell types, including neutrophils, macrophages, dendritic cells, and monocytes but also unexpected cell populations with immunosuppressive and pro-tumour roles. Indeed, the release of tumour-derived factors influences physiological haematopoiesis producing unconventional cells with immunosuppressive and tolerogenic functions such as myeloid-derived suppressor cells. These pro-tumour myeloid cell populations not only support immune escape directly but also assist tumour invasion trough non-immunological activities. It is therefore not surprising that these cell subsets considerably impact in tumour progression and cancer therapy resistance, including immunotherapy, and are being investigated as potential targets for developing a new era of cancer therapy. In this review, we discuss emerging strategies able to modulate the functional activity of these tumour-supporting myeloid cells subverting their accumulation, recruitment, survival, and functions. These innovative approaches will help develop innovative, or improve existing, cancer treatments.

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“…In 2015, Casbon et al demonstrated that breast-cancer-derived G-CSF induced the substantial remodeling of hematopoiesis, which resulted in myeloid cell expansion and concurrent anemia. More recently, Long et al built on this work by showing that tumor-derived GM-CSF reprograms the developmental potential of erythroid precursor cells, resulting in their acquisition of a myeloid phenotype and immune suppressive function [ 12 ]. AML blast-derived IL-6 was recently found to inhibit erythropoiesis at the erythroblast phase, resulting in severe anemia independent of the BM blast percent [ 116 ].…”

Section: Future Perspectivesmentioning

confidence: 99%

“…A population of monocytic lineage cells that are capable of differentiating into PMN-MDSCs has been identified, and this population was significantly expanded in the setting of cancer [ 11 ]. Furthermore, Long et al recently showed that, in the presence of cancer, erythropoiesis is altered to favor the development of myeloid cells capable of inhibiting T cell responses over normal erythroid cells, resulting in further immune suppression and anemia [ 12 ]. These findings open exciting new lines of investigation to better understand how cancer affects hematopoiesis, as well as how to target this process for therapeutic benefit.…”

Section: Introductionmentioning

confidence: 99%

Myeloid-Derived Suppressor Cells: New Insights into the Pathogenesis and Therapy of MDS

Velegraki

Stiff

Papadaki

et al. 2022

JCM

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Myelodysplastic syndromes (MDS) are hematopoietic malignancies characterized by the clonal expansion of hematopoietic stem cells, bone marrow failure manifested by cytopenias, and increased risk for evolving to acute myeloid leukemia. Despite the fact that the acquisition of somatic mutations is considered key for the initiation of the disease, the bone marrow microenvironment also plays significant roles in MDS by providing the right niche and even shaping the malignant clone. Aberrant immune responses are frequent in MDS and are implicated in many aspects of MDS pathogenesis. Recently, myeloid-derived suppressor cells (MDSCs) have gained attention for their possible implication in the immune dysregulation associated with MDS. Here, we summarize the key findings regarding the expansion of MDSCs in MDS, their role in MDS pathogenesis and immune dysregulation, as well their potential as a new therapeutic target for MDS.

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Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy

Cited by 76 publications

References 101 publications

Hematologic dysfunction in cancer: Mechanisms, effects on antitumor immunity, and roles in disease progression

Hematologic dysfunction in cancer: Mechanisms, effects on antitumor immunity, and roles in disease progression

Targeting tumour-reprogrammed myeloid cells: the new battleground in cancer immunotherapy

Myeloid-Derived Suppressor Cells: New Insights into the Pathogenesis and Therapy of MDS

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