Therapeutic Efficacy of CD34-Derived Allogeneic Dendritic Cells Engineered to Express CD93, CD40L, and CXCL13 in Humanized Mouse Models of Pancreatic Cancer
<b>Background/Objectives</b>: Pancreatic cancer remains the fourth leading cause of cancer-related deaths. While peripheral blood-derived mature dendritic cell (mDC) vaccines have shown potential in eliciting anti-tumor immune responses, clinical efficacy has been limited. This study aim...
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MDPI AG
2025-07-01
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| Online Access: | https://www.mdpi.com/2076-393X/13/7/749 |
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| author | Sara Huerta-Yepez Jose D. Gonzalez Neha Sheik Senay Beraki Elango Kathirvel Ariel Rodriguez-Frandsen Po-Chun Chen Tiran Sargsyan Saleemulla Mahammad Mark R. Dybul Lu Chen Francois Binette Anahid Jewett |
| author_facet | Sara Huerta-Yepez Jose D. Gonzalez Neha Sheik Senay Beraki Elango Kathirvel Ariel Rodriguez-Frandsen Po-Chun Chen Tiran Sargsyan Saleemulla Mahammad Mark R. Dybul Lu Chen Francois Binette Anahid Jewett |
| author_sort | Sara Huerta-Yepez |
| collection | DOAJ |
| description | <b>Background/Objectives</b>: Pancreatic cancer remains the fourth leading cause of cancer-related deaths. While peripheral blood-derived mature dendritic cell (mDC) vaccines have shown potential in eliciting anti-tumor immune responses, clinical efficacy has been limited. This study aimed to enhance the potency and scalability of DC-based immunotherapy by developing an allogeneic DC platform derived from CD34<sup>+</sup> hematopoietic stem cells (HSCs), genetically engineered to overexpress CD93, CD40L, and CXCL13, followed by maturation and tumor antigen pulsing. <b>Methods</b>: Engineered DCs were generated from CD34<sup>+</sup> HSCs and matured in vitro after lentiviral transduction of CD93, CD40L, and CXCL13. Tumor lysates were used for antigen pulsing. A scrambled-sequence control DC was used for comparison. In vitro assays were performed to assess T cell activation and tumor cell killing. In vivo efficacy was evaluated using orthotopic pancreatic tumors in BLT and PBMC-humanized NSG mice established with the MiaPaca-2 (MP2) cell line. <b>Results</b>: Engineered DCs significantly enhanced T cell activation and tumor-specific cytotoxicity in vitro compared to control DCs. Antigen pulsing further amplified immune activation. In vivo, treated humanized mice showed increased CD4<sup>+</sup>, CD8<sup>+</sup>, and NK cell frequencies in peripheral blood and within tumors, correlating with reduced tumor burden. <b>Conclusions</b>: Our data shows that the antigen-pulsed, engineered DCs have the potency to activate immune cells, which leads to a significant reduction in pancreatic tumors and therefore could potentially provide an effective therapeutic opportunity for the treatment of pancreatic cancer and other solid tumors. |
| format | Article |
| id | doaj-art-bb7949acb74c43b0b0845a25eace45c4 |
| institution | Kabale University |
| issn | 2076-393X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Vaccines |
| spelling | doaj-art-bb7949acb74c43b0b0845a25eace45c42025-08-20T03:32:16ZengMDPI AGVaccines2076-393X2025-07-0113774910.3390/vaccines13070749Therapeutic Efficacy of CD34-Derived Allogeneic Dendritic Cells Engineered to Express CD93, CD40L, and CXCL13 in Humanized Mouse Models of Pancreatic CancerSara Huerta-Yepez0Jose D. Gonzalez1Neha Sheik2Senay Beraki3Elango Kathirvel4Ariel Rodriguez-Frandsen5Po-Chun Chen6Tiran Sargsyan7Saleemulla Mahammad8Mark R. Dybul9Lu Chen10Francois Binette11Anahid Jewett12Division of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, School of Dentistry, University of California, 10833 Le Conte Ave, Los Angeles, CA 90095, USARenovaro Biosciences, 2080 Century Park East, Suite 906, Los Angeles, CA 90067, USARenovaro Biosciences, 2080 Century Park East, Suite 906, Los Angeles, CA 90067, USARenovaro Biosciences, 2080 Century Park East, Suite 906, Los Angeles, CA 90067, USARenovaro Biosciences, 2080 Century Park East, Suite 906, Los Angeles, CA 90067, USARenovaro Biosciences, 2080 Century Park East, Suite 906, Los Angeles, CA 90067, USADivision of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, School of Dentistry, University of California, 10833 Le Conte Ave, Los Angeles, CA 90095, USADivision of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, School of Dentistry, University of California, 10833 Le Conte Ave, Los Angeles, CA 90095, USARenovaro Biosciences, 2080 Century Park East, Suite 906, Los Angeles, CA 90067, USAThe Center for Global Health Practice and Impact, Georgetown University Medical Center, 500 First Street, NW, Washington, DC 20002, USARenovaro Biosciences, 2080 Century Park East, Suite 906, Los Angeles, CA 90067, USARenovaro Biosciences, 2080 Century Park East, Suite 906, Los Angeles, CA 90067, USADivision of Oral Biology and Medicine, The Jane and Jerry Weintraub Center for Reconstructive Biotechnology, School of Dentistry, University of California, 10833 Le Conte Ave, Los Angeles, CA 90095, USA<b>Background/Objectives</b>: Pancreatic cancer remains the fourth leading cause of cancer-related deaths. While peripheral blood-derived mature dendritic cell (mDC) vaccines have shown potential in eliciting anti-tumor immune responses, clinical efficacy has been limited. This study aimed to enhance the potency and scalability of DC-based immunotherapy by developing an allogeneic DC platform derived from CD34<sup>+</sup> hematopoietic stem cells (HSCs), genetically engineered to overexpress CD93, CD40L, and CXCL13, followed by maturation and tumor antigen pulsing. <b>Methods</b>: Engineered DCs were generated from CD34<sup>+</sup> HSCs and matured in vitro after lentiviral transduction of CD93, CD40L, and CXCL13. Tumor lysates were used for antigen pulsing. A scrambled-sequence control DC was used for comparison. In vitro assays were performed to assess T cell activation and tumor cell killing. In vivo efficacy was evaluated using orthotopic pancreatic tumors in BLT and PBMC-humanized NSG mice established with the MiaPaca-2 (MP2) cell line. <b>Results</b>: Engineered DCs significantly enhanced T cell activation and tumor-specific cytotoxicity in vitro compared to control DCs. Antigen pulsing further amplified immune activation. In vivo, treated humanized mice showed increased CD4<sup>+</sup>, CD8<sup>+</sup>, and NK cell frequencies in peripheral blood and within tumors, correlating with reduced tumor burden. <b>Conclusions</b>: Our data shows that the antigen-pulsed, engineered DCs have the potency to activate immune cells, which leads to a significant reduction in pancreatic tumors and therefore could potentially provide an effective therapeutic opportunity for the treatment of pancreatic cancer and other solid tumors.https://www.mdpi.com/2076-393X/13/7/749CD34 hematopoietic stem cellsdendritic cell therapyCD40LCD93CXCL13pancreatic cancer |
| spellingShingle | Sara Huerta-Yepez Jose D. Gonzalez Neha Sheik Senay Beraki Elango Kathirvel Ariel Rodriguez-Frandsen Po-Chun Chen Tiran Sargsyan Saleemulla Mahammad Mark R. Dybul Lu Chen Francois Binette Anahid Jewett Therapeutic Efficacy of CD34-Derived Allogeneic Dendritic Cells Engineered to Express CD93, CD40L, and CXCL13 in Humanized Mouse Models of Pancreatic Cancer Vaccines CD34 hematopoietic stem cells dendritic cell therapy CD40L CD93 CXCL13 pancreatic cancer |
| title | Therapeutic Efficacy of CD34-Derived Allogeneic Dendritic Cells Engineered to Express CD93, CD40L, and CXCL13 in Humanized Mouse Models of Pancreatic Cancer |
| title_full | Therapeutic Efficacy of CD34-Derived Allogeneic Dendritic Cells Engineered to Express CD93, CD40L, and CXCL13 in Humanized Mouse Models of Pancreatic Cancer |
| title_fullStr | Therapeutic Efficacy of CD34-Derived Allogeneic Dendritic Cells Engineered to Express CD93, CD40L, and CXCL13 in Humanized Mouse Models of Pancreatic Cancer |
| title_full_unstemmed | Therapeutic Efficacy of CD34-Derived Allogeneic Dendritic Cells Engineered to Express CD93, CD40L, and CXCL13 in Humanized Mouse Models of Pancreatic Cancer |
| title_short | Therapeutic Efficacy of CD34-Derived Allogeneic Dendritic Cells Engineered to Express CD93, CD40L, and CXCL13 in Humanized Mouse Models of Pancreatic Cancer |
| title_sort | therapeutic efficacy of cd34 derived allogeneic dendritic cells engineered to express cd93 cd40l and cxcl13 in humanized mouse models of pancreatic cancer |
| topic | CD34 hematopoietic stem cells dendritic cell therapy CD40L CD93 CXCL13 pancreatic cancer |
| url | https://www.mdpi.com/2076-393X/13/7/749 |
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