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Published on: November 28, 2019
Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1
Haixia Long1, Qingzhu Jia1, Liuyang Wang2
1Institute of Cancer, Xinqiao Hospital, Third Military Medical University, Chongqing, China; Chongqing Key Laboratory of Immunotherapy, Chongqing, China.
Abstract:
Despite the unprecedented success of immune checkpoint inhibitors (ICIs) as anti-cancer therapy, it remains a prevailing clinical need to identify additional mechanisms underlying ICI therapeutic efficacy and potential drug resistance. Here, using lineage tracking in cancer patients and tumor-bearing mice, we demonstrate that erythroid progenitor cells lose their developmental potential and switch to the myeloid lineage. Single-cell transcriptome analyses reveal that, notwithstanding quantitative differences in erythroid gene expression, erythroid differentiated myeloid cells (EDMCs) are transcriptionally indistinguishable from their myeloid-originated counterparts. EDMCs possess multifaceted machinery to curtail T cell-mediated anti-tumor responses. Consequently, EDMC content within tumor tissues is negatively associated with T cell inflammation for the majority of solid cancers; moreover, EDMC enrichment, in accordance with anemia manifestation, is predictive of poor prognosis in various cohorts of patients undergoing ICI therapy. Together, our findings reveal a feedforward mechanism by which tumors exploit anemia-triggered erythropoiesis for myeloid transdifferentiation and immunosuppression.
Insights
Tumors exploit anemia to trigger red blood cell precursors to become immunosuppressive myeloid cells. This myeloid cell enrichment predicts poor response to immune checkpoint inhibitors (ICIs) in cancer patients.
Area of Science:
- Oncology
- Immunology
- Hematology
Background:
- Immune checkpoint inhibitors (ICIs) have transformed cancer therapy.
- Understanding resistance mechanisms to ICIs is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate novel mechanisms of ICI resistance.
- To identify cellular players contributing to an immunosuppressive tumor microenvironment.
Main Methods:
- Lineage tracking in cancer patients and tumor-bearing mice.
- Single-cell transcriptome analysis.
- Correlation of cell populations with clinical data and patient prognosis.
Main Results:
- Erythroid progenitor cells can transdifferentiate into myeloid cells (EDMCs) under tumor influence.
- EDMCs exhibit immunosuppressive properties, curtailing T cell anti-tumor activity.
- EDMC enrichment in tumors correlates with reduced T cell inflammation and predicts poor prognosis in patients receiving ICIs, especially in conjunction with anemia.
Conclusions:
- Tumors can hijack anemia-induced erythropoiesis to generate immunosuppressive myeloid cells.
- This mechanism represents a novel pathway for ICI resistance and tumor immune evasion.
- Targeting this erythropoiesis-driven myeloid transdifferentiation may offer new therapeutic strategies for cancer treatment.
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