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Cited by 6Immune cells in cancerImmunotherapy and Immune ResponsesCancer Immunotherapy and Biomarkers

Mitigating the Prevalence and Function of Myeloid‐derived Suppressor Cells by Redirecting Myeloid Differentiation Using a Novel Immune Modulator

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Oliver, Liliana, Alvarez, Rydell, Diaz, Raquel, Valdés, Anet, Colligan, Sean H, Nemeth, Michael J, Twum, Danielle Y F, Fernández, Audry +12 more·2022·Journal for ImmunoTherapy of Cancer
DOI 10.1136/jitc-2022-004710PMC PMC9511656
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Abstract

Background: Immune suppression is common in neoplasia and a major driver is tumor-induced myeloid dysfunction. Yet, overcoming such myeloid cell defects remains an untapped strategy to reverse suppression and improve host defense. Exposure of bone marrow progenitors to heightened levels of myeloid growth factors in cancer or following certain systemic treatments promote abnormal myelopoiesis characterized by the production of myeloid-derived suppressor cells (MDSCs) and a deficiency in antigen-presenting cell function. We previously showed that a novel immune modulator, termed ‘very small size particle’ (VSSP), attenuates MDSC function in tumor-bearing mice, which was accompanied by an increase in dendritic cells (DCs) suggesting that VSSP exhibits myeloid differentiating properties. Therefore, here, we addressed two unresolved aspects of the mechanism of action of this unique immunomodulatory agent: (1) does VSSP alter myelopoiesis in the bone marrow to redirect MDSC differentiation toward a monocyte/macrophage or DC fate? and (2) does VSSP mitigate the frequency and suppressive function of human tumor-induced MDSCs? Methods: To address the first question, we first used a murine model of granulocyte-colony stimulating factor-driven emergency myelopoiesis following chemotherapy-induced myeloablation, which skews myeloid output toward MDSCs, especially the polymorphonuclear (PMN)-MDSC subset. Following VSSP treatment, progenitors and their myeloid progeny were analyzed by immunophenotyping and MDSC function was evaluated by suppression assays. To strengthen rigor, we validated our findings in tumor-bearing mouse models. To address the second question, we conducted a clinical trial in patients with metastatic renal cell carcinoma, wherein 15 patients were treated with VSSP. Endpoints in this study included safety and impact on PMN-MDSC frequency and function. Results: We demonstrated that VSSP diminished PMN-MDSCs by shunting granulocyte-monocyte progenitor differentiation toward monocytes/macrophages and DCs with heightened expression of the myeloid-dependent transcription factors interferon regulatory factor-8 and PU.1. This skewing was at the expense of expansion of granulocytic progenitors and rendered the remaining MDSCs less suppressive. Importantly, these effects were also demonstrated in a clinical setting wherein VSSP monotherapy significantly reduced circulating PMN-MDSCs, and their suppressive function. Conclusions: Altogether, these data revealed VSSP as a novel regulator of myeloid biology that mitigates MDSCs in cancer patients and reinstates a more normal myeloid phenotype that potentially favors immune activation over immune suppression.

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  • Microglial transcription factors are broadly expressed across myeloid lineages.

    “these transcription factors are broadly expressed across myeloid lineages”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [75]

    The Introduction identifies IRF8 and PU.1 as regulators of myeloid differentiation, and the Results report their expression in monocytes, macrophages, and dendritic cells. Those passages support expression in several myeloid cell types, but the paper does not address microglia or establish broad expression across myeloid lineages. Page numbers are unavailable in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Systemic modulation of microglial transcription factors risks disrupting peripheral immunity.

    “systemic modulation risks disrupting peripheral immunity”

    From Targeting Microglial Transcriptional Reprogramming as a Therapy Strategy for Alzheimer's Disease (2026) · cites this paper as [75]

    The Introduction and Discussion describe IRF8 and PU.1 in myeloid differentiation and the immune effects of VSSP, but do not address systemic modulation of microglial transcription factors or a risk of disrupting peripheral immunity. A search for adverse peripheral immune effects found a Results passage reporting that VSSP was well tolerated, which does not settle the claimed risk. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Oliver, L., Alvarez, R., Diaz, R., Valdés, A., Colligan, S. H., Nemeth, M. J., Twum, D. Y. F., Fernández, A., Fernández-Medina, O., Carlson, L. M., Yu, H., Eng, K. H., Hensen, M. L., Rábade-Chediak, M. L., Fernández, L. E., Lee, K. P., Perez, L., Muhitch, J. B., Mesa, C., & Abrams, S. I.
Affiliations
  • Center of Molecular Immunology (Cuba) (CU)
  • Department of Immunoregulation, Immunology and Immunotherapy Direction, Center of Molecular Immunology, Havana, Cuba
  • Department of Oncology, Joaquín Albarrán Hospital, Havana, Cuba
  • Roswell Park Comprehensive Cancer Center (US)
  • Indiana University Health (US)
  • Clinical Direction, Center of Molecular Immunology, Havana, Cuba
Corresponding author
  • Muhitch, Jason B
  • Mesa, Circe
  • Abrams, Scott I
ORCID
Venue
Journal for ImmunoTherapy of Cancer
Publisher
BMJ
Published
2022-09
Volume
10
Issue
9
Pages
e004710
ISSN
2051-1426 (ISSN-L)
DOI
10.1136/jitc-2022-004710
PMC
PMC9511656
OpenAlex
W4296818781
Cited by
6
References
1
Citations by year
2025: 2 · 2024: 2 · 2023: 2
FWCI
0.57
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal for ImmunoTherapy of Cancer (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Center of Molecular Immunology, Havana, Cuba
  • Roswell Park Cancer Institute
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
  • Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
  • Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
Keywords
myeloid-derived suppressor cells, immunomodulators, myelopoiesis, dendritic cells, monocyte-to-macrophage differentiation, granulocyte colony-stimulating factor, IRF8, PU.1, polymorphonuclear MDSCs, renal cell carcinoma, tumor immunosuppression, bone marrow progenitor cells, clinical trial safety and efficacy, metastatic renal cell carcinoma, cancer immunotherapy
MeSH terms
Myeloid-Derived Suppressor Cells, Carcinoma, Renal Cell, Humans, Kidney Neoplasms, Prevalence

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