PSMA antibody, humanized PSMA.CAR10.3, or Cetuximab increases prostate cancer localization of NF-κB p50-deficient immature myeloid cells (p50-IMC) and phagocytosis by their macrophage progeny
Abstract Adoptive transfer of immature myeloid cells lacking the repressive NF-κB p50 subunit (p50-IMC) slows the growth of syngeneic murine prostate cancer and other tumors. Directing p50-IMC to tumors using Fc receptor-bound antibodies (Abs) or surface chimeric antigen receptors (CARs) may increas...
Saved in:
| Main Authors: | , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Springer
2025-02-01
|
| Series: | Cancer Immunology, Immunotherapy |
| Subjects: | |
| Online Access: | https://doi.org/10.1007/s00262-024-03939-4 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1823862125526777856 |
|---|---|
| author | Mohammad A. Alzubi Theresa Barberi Alan D. Friedman |
| author_facet | Mohammad A. Alzubi Theresa Barberi Alan D. Friedman |
| author_sort | Mohammad A. Alzubi |
| collection | DOAJ |
| description | Abstract Adoptive transfer of immature myeloid cells lacking the repressive NF-κB p50 subunit (p50-IMC) slows the growth of syngeneic murine prostate cancer and other tumors. Directing p50-IMC to tumors using Fc receptor-bound antibodies (Abs) or surface chimeric antigen receptors (CARs) may increase tumor localization and subsequent phagocytosis of cancer cells by their mature myeloid progeny, potentiating anti-tumor T cell activation. PSMA and EGFR are found on aggressive human prostate cancers, and p50-IMC express receptors that bind the antibody Fc domain. p50-IMC combined with PSMA Ab, EGFR Ab (Cetuximab), or fully humanized PSMA.CAR10.3 manifest increased localization to Myc-CaP murine prostate cancer tumors expressing PSMA or EGFR. Tumor localization is further increased when myelo-depleting 5-fluorouracil precedes p50-IMC administration. Additionally, we find that PSMA Ab, EGFR Ab, or PSMA.CAR10.3 increase in vitro phagocytosis of Myc-CaP cells expressing PSMA or EGFR by p50-IMC-derived macrophages, including in M2-promoting IL-4, which is a component of the immune-suppressive tumor microenvironment. Lack of tolerance of human PSMA or EGFR by immune-competent mice and lack of expression of human PSMA protein in the prostate of AR2-Probasin-hPSMA transgenic mice precluded our ability to determine whether human-specific PSMA or EGFR antibody or PSMA.CAR10.3 increases anti-tumor efficacy of murine p50-IMC. Nevertheless, this study indicates the potential clinical utility of adding a tumor-directing antibody or CAR, including the novel, fully humanized PSMA.CAR10.3, to proinflammatory p50-IMC to optimize the activation of anti-tumor immunity in prostate cancer and other malignancies, and understanding PSMA toxicity in normal but not malignant prostate epithelium may reveal a novel therapeutic opportunity. |
| format | Article |
| id | doaj-art-1a6c19192ea449b48da7d58562346e73 |
| institution | Kabale University |
| issn | 1432-0851 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Springer |
| record_format | Article |
| series | Cancer Immunology, Immunotherapy |
| spelling | doaj-art-1a6c19192ea449b48da7d58562346e732025-02-09T12:39:07ZengSpringerCancer Immunology, Immunotherapy1432-08512025-02-0174311210.1007/s00262-024-03939-4PSMA antibody, humanized PSMA.CAR10.3, or Cetuximab increases prostate cancer localization of NF-κB p50-deficient immature myeloid cells (p50-IMC) and phagocytosis by their macrophage progenyMohammad A. Alzubi0Theresa Barberi1Alan D. Friedman2Division of Pediatric Oncology, Department of Oncology, Johns Hopkins UniversityDivision of Pediatric Oncology, Department of Oncology, Johns Hopkins UniversityDivision of Pediatric Oncology, Department of Oncology, Johns Hopkins UniversityAbstract Adoptive transfer of immature myeloid cells lacking the repressive NF-κB p50 subunit (p50-IMC) slows the growth of syngeneic murine prostate cancer and other tumors. Directing p50-IMC to tumors using Fc receptor-bound antibodies (Abs) or surface chimeric antigen receptors (CARs) may increase tumor localization and subsequent phagocytosis of cancer cells by their mature myeloid progeny, potentiating anti-tumor T cell activation. PSMA and EGFR are found on aggressive human prostate cancers, and p50-IMC express receptors that bind the antibody Fc domain. p50-IMC combined with PSMA Ab, EGFR Ab (Cetuximab), or fully humanized PSMA.CAR10.3 manifest increased localization to Myc-CaP murine prostate cancer tumors expressing PSMA or EGFR. Tumor localization is further increased when myelo-depleting 5-fluorouracil precedes p50-IMC administration. Additionally, we find that PSMA Ab, EGFR Ab, or PSMA.CAR10.3 increase in vitro phagocytosis of Myc-CaP cells expressing PSMA or EGFR by p50-IMC-derived macrophages, including in M2-promoting IL-4, which is a component of the immune-suppressive tumor microenvironment. Lack of tolerance of human PSMA or EGFR by immune-competent mice and lack of expression of human PSMA protein in the prostate of AR2-Probasin-hPSMA transgenic mice precluded our ability to determine whether human-specific PSMA or EGFR antibody or PSMA.CAR10.3 increases anti-tumor efficacy of murine p50-IMC. Nevertheless, this study indicates the potential clinical utility of adding a tumor-directing antibody or CAR, including the novel, fully humanized PSMA.CAR10.3, to proinflammatory p50-IMC to optimize the activation of anti-tumor immunity in prostate cancer and other malignancies, and understanding PSMA toxicity in normal but not malignant prostate epithelium may reveal a novel therapeutic opportunity.https://doi.org/10.1007/s00262-024-03939-4MyeloidImmunotherapyNF-κB p50Prostate cancerPSMAEGFR |
| spellingShingle | Mohammad A. Alzubi Theresa Barberi Alan D. Friedman PSMA antibody, humanized PSMA.CAR10.3, or Cetuximab increases prostate cancer localization of NF-κB p50-deficient immature myeloid cells (p50-IMC) and phagocytosis by their macrophage progeny Cancer Immunology, Immunotherapy Myeloid Immunotherapy NF-κB p50 Prostate cancer PSMA EGFR |
| title | PSMA antibody, humanized PSMA.CAR10.3, or Cetuximab increases prostate cancer localization of NF-κB p50-deficient immature myeloid cells (p50-IMC) and phagocytosis by their macrophage progeny |
| title_full | PSMA antibody, humanized PSMA.CAR10.3, or Cetuximab increases prostate cancer localization of NF-κB p50-deficient immature myeloid cells (p50-IMC) and phagocytosis by their macrophage progeny |
| title_fullStr | PSMA antibody, humanized PSMA.CAR10.3, or Cetuximab increases prostate cancer localization of NF-κB p50-deficient immature myeloid cells (p50-IMC) and phagocytosis by their macrophage progeny |
| title_full_unstemmed | PSMA antibody, humanized PSMA.CAR10.3, or Cetuximab increases prostate cancer localization of NF-κB p50-deficient immature myeloid cells (p50-IMC) and phagocytosis by their macrophage progeny |
| title_short | PSMA antibody, humanized PSMA.CAR10.3, or Cetuximab increases prostate cancer localization of NF-κB p50-deficient immature myeloid cells (p50-IMC) and phagocytosis by their macrophage progeny |
| title_sort | psma antibody humanized psma car10 3 or cetuximab increases prostate cancer localization of nf κb p50 deficient immature myeloid cells p50 imc and phagocytosis by their macrophage progeny |
| topic | Myeloid Immunotherapy NF-κB p50 Prostate cancer PSMA EGFR |
| url | https://doi.org/10.1007/s00262-024-03939-4 |
| work_keys_str_mv | AT mohammadaalzubi psmaantibodyhumanizedpsmacar103orcetuximabincreasesprostatecancerlocalizationofnfkbp50deficientimmaturemyeloidcellsp50imcandphagocytosisbytheirmacrophageprogeny AT theresabarberi psmaantibodyhumanizedpsmacar103orcetuximabincreasesprostatecancerlocalizationofnfkbp50deficientimmaturemyeloidcellsp50imcandphagocytosisbytheirmacrophageprogeny AT alandfriedman psmaantibodyhumanizedpsmacar103orcetuximabincreasesprostatecancerlocalizationofnfkbp50deficientimmaturemyeloidcellsp50imcandphagocytosisbytheirmacrophageprogeny |