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CD71(+) erythroid cells suppress T-cell effector functions and predict immunotherapy outcomes in patients with virus-associated solid tumors

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 hypoth...

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Autores principales: Bozorgmehr, Najmeh, Okoye, Isobel, Mashhouri, Siavash, Lu, Julia, Koleva, Petya, Walker, John, Elahi, Shokrollah
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10230995/
https://www.ncbi.nlm.nih.gov/pubmed/37236637
http://dx.doi.org/10.1136/jitc-2022-006595
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author Bozorgmehr, Najmeh
Okoye, Isobel
Mashhouri, Siavash
Lu, Julia
Koleva, Petya
Walker, John
Elahi, Shokrollah
author_facet Bozorgmehr, Najmeh
Okoye, Isobel
Mashhouri, Siavash
Lu, Julia
Koleva, Petya
Walker, John
Elahi, Shokrollah
author_sort Bozorgmehr, Najmeh
collection PubMed
description 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.
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spelling pubmed-102309952023-06-01 CD71(+) erythroid cells suppress T-cell effector functions and predict immunotherapy outcomes in patients with virus-associated solid tumors Bozorgmehr, Najmeh Okoye, Isobel Mashhouri, Siavash Lu, Julia Koleva, Petya Walker, John Elahi, Shokrollah J Immunother Cancer Immunotherapy Biomarkers 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. BMJ Publishing Group 2023-05-26 /pmc/articles/PMC10230995/ /pubmed/37236637 http://dx.doi.org/10.1136/jitc-2022-006595 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. https://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/ (https://creativecommons.org/licenses/by-nc/4.0/) .
spellingShingle Immunotherapy Biomarkers
Bozorgmehr, Najmeh
Okoye, Isobel
Mashhouri, Siavash
Lu, Julia
Koleva, Petya
Walker, John
Elahi, Shokrollah
CD71(+) erythroid cells suppress T-cell effector functions and predict immunotherapy outcomes in patients with virus-associated solid tumors
title CD71(+) erythroid cells suppress T-cell effector functions and predict immunotherapy outcomes in patients with virus-associated solid tumors
title_full CD71(+) erythroid cells suppress T-cell effector functions and predict immunotherapy outcomes in patients with virus-associated solid tumors
title_fullStr CD71(+) erythroid cells suppress T-cell effector functions and predict immunotherapy outcomes in patients with virus-associated solid tumors
title_full_unstemmed CD71(+) erythroid cells suppress T-cell effector functions and predict immunotherapy outcomes in patients with virus-associated solid tumors
title_short CD71(+) erythroid cells suppress T-cell effector functions and predict immunotherapy outcomes in patients with virus-associated solid tumors
title_sort cd71(+) erythroid cells suppress t-cell effector functions and predict immunotherapy outcomes in patients with virus-associated solid tumors
topic Immunotherapy Biomarkers
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10230995/
https://www.ncbi.nlm.nih.gov/pubmed/37236637
http://dx.doi.org/10.1136/jitc-2022-006595
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