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Updated: Jul 29, 2025
Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
Published on: March 7, 2025
CD71+ erythroid cells suppress T-cell effector functions and predict immunotherapy outcomes in patients with
Najmeh Bozorgmehr1, Isobel Okoye1, Siavash Mashhouri1
1Department of Dentistry, Faculty of Medicine & Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Background:
Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer. However, only a portion of patients respond to such treatments. Therefore, it remains a prevailing clinical need to identify factors associated with acquired resistance or lack of response to ICIs. We hypothesized that the immunosuppressive CD71+ erythroid cells (CECs) within the tumor and/or distant 'out-of-field' may impair antitumor response.
Methods:
We studied 38 patients with cancer through a phase II clinical trial investigating the effects of oral valproate combined with avelumab (anti-programmed death-ligand 1 (PD-L1)) in virus-associated solid tumors (VASTs). We quantified the frequency/functionality of CECs in blood and biopsies of patients. Also, we established an animal model of melanoma (B16-F10) to investigate the possible effects of erythropoietin (EPO) treatment on anti-PD-L1 therapy.
Results:
We found a substantial expansion of CECs in the blood of patients with VAST compared with healthy controls. We noted that the frequency of CECs in circulation was significantly higher at the baseline and throughout the study in non-responders versus responders to PD-L1 therapy. Moreover, we observed that CECs in a dose-dependent manner suppress effector functions of autologous T cells in vitro. The subpopulation of CD45+CECs appears to have a more robust immunosuppressive property compared with their CD45- counterparts. This was illustrated by a stronger expression of reactive oxygen species, PD-L1/PD-L2, and V-domain Ig suppressor of T-cell activation in this subpopulation. Lastly, we found a higher frequency of CECs in the blood circulation at the later cancer stage and their abundance was associated with anemia, and a poor response to immunotherapy. Finally, we report the expansion of CECs in the spleen and tumor microenvironment of mice with melanoma. We found that although CECs in tumor-bearing mice secret artemin, this was not the case for VAST-derived CECs in humans. Notably, our results imply that EPO, a frequently used drug for anemia treatment in patients with cancer, may promote the generation of CECs and subsequently abrogates the therapeutic effects of ICIs (eg, anti-PD-L1).
Conclusions:
Our results demonstrate that anemia by the expansion of CECs may enhance cancer progression. Notably, measuring the frequency of CECs may serve as a valuable biomarker to predict immunotherapy outcomes.
Insights
Expanded CD71+ erythroid cells (CECs) are linked to poor responses to cancer immunotherapy. Measuring CECs may predict patient outcomes and inform treatment strategies against immune checkpoint inhibitors.
Area of Science:
- Immunology
- Oncology
- Hematology
Background:
- Immune checkpoint inhibitors (ICIs) have transformed cancer treatment but benefit only a subset of patients.
- Identifying resistance factors to ICIs is crucial for improving patient outcomes.
- The role of immunosuppressive CD71+ erythroid cells (CECs) in ICI resistance is under investigation.
Purpose of the Study:
- To investigate the association between CECs and response to anti-PD-L1 therapy in cancer patients.
- To explore the immunosuppressive function of CECs and their potential role in immunotherapy resistance.
- To examine the impact of erythropoietin (EPO) on CECs and ICI efficacy.
Main Methods:
- A phase II clinical trial involving 38 cancer patients treated with valproate and avelumab (anti-PD-L1).
- Quantification of CEC frequency and function in patient blood and biopsies.
- Establishment of a murine melanoma model to study EPO's effect on anti-PD-L1 therapy.
Main Results:
- CECs were expanded in patients with virus-associated solid tumors (VASTs) compared to healthy controls.
- Higher CEC frequency correlated with non-response to PD-L1 therapy and was associated with anemia and later cancer stages.
- CECs, particularly CD45+ subpopulations, suppressed T-cell effector functions in vitro, expressing immunosuppressive molecules.
- EPO treatment in mice increased CECs, potentially abrogating anti-PD-L1 efficacy.
Conclusions:
- Anemia driven by CEC expansion may promote cancer progression and immunotherapy resistance.
- CEC frequency serves as a potential biomarker for predicting immunotherapy outcomes.
- Targeting CECs or mitigating EPO's effects could enhance cancer immunotherapy efficacy.
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