1. Proinflammatory allogeneic dendritic cells enhance the therapeutic efficacy of systemic anti-4-1BB treatment.
- Author
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Ali, Arwa, Gao, Menghan, Iskantar, Alexandros, Hai Wang, Karlsson-Parra, Alex, Di Yu, and Chuan Jin
- Subjects
DENDRITIC cells ,SUPPRESSOR cells ,TREATMENT effectiveness ,KILLER cells ,CANCER cells - Abstract
As an immune adjuvant, proinflammatory allogeneic dendritic cells (AlloDCs) have demonstrated promising immune-priming effects in several preclinical and clinical studies. The effector cells, including NK cells and T cells are widely acknowledged as pivotal factors in the effectiveness of cancer immunotherapy due to their ability to selectively identify and eradicate malignant cells. 4-1BB, as a costimulatory receptor, plays a significant role in the stimulation of effector cell activation. This study evaluated the anti-tumor effects when combining intratumoral administration of the immune-adjuvant AlloDCs with systemic a4-1BB treatment directly acting on effector cells. In both the CT-26 murine colon carcinoma model and B16 murine melanoma model, AlloDCs demonstrated a significant enhancement in the therapeutic efficacy of α4-1BB antibody. This enhancement was observed through the delayed growth of tumors and prolonged survival. Analysis of the tumor microenvironment (TME) in the combined-treatment group revealed an immune-inflamed TME characterized by increased infiltration of activated endogenous DCs and IFNg+ CD8
+ T cells, showing reduced signs of exhaustion. Furthermore, there was an augmented presence of tissue-resident memory (TRM) CD8+ T cells (CD103+ CD49a+ CD69+ ). The combination treatment also led to increased infiltration of CD39+ CD103+ tumor-specific CD8+ T cells and neoantigenspecific T cells into the tumor. Additionally, the combined treatment resulted in a less immunosuppressive TME, indicated by decreased infiltration of myeloidderived suppressor cells and Tregs. These findings suggest that the combination of intratumoral AlloDCs administration with systemic agonistic α4-1BB treatment can generate a synergistic anti-tumor response, thereby warranting further investigation through clinical studies. [ABSTRACT FROM AUTHOR]- Published
- 2023
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