| 1. |
- Ali, Arwa, et al.
(författare)
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Proinflammatory allogeneic dendritic cells enhance the therapeutic efficacy of systemic anti-4-1BB treatment
- 2023
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 14
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Tidskriftsartikel (refereegranskat)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 a4-1BB 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 IFN?(+) CD8(+) T cells, showing reduced signs of exhaustion. Furthermore, there was an augmented presence of tissue-resident memory (T-RM) CD8(+) T cells (CD103(+)CD49a(+)CD69(+)). The combination treatment also led to increased infiltration of CD39(+)CD103(+) tumor-specific CD8(+) T cells and neoantigen-specific T cells into the tumor. Additionally, the combined treatment resulted in a less immunosuppressive TME, indicated by decreased infiltration of myeloid-derived suppressor cells and Tregs. These findings suggest that the combination of intratumoral AlloDCs administration with systemic agonistic a4-1BB treatment can generate a synergistic anti-tumor response, thereby warranting further investigation through clinical studies.
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| 2. |
- Jin, Chuan, 1986-, et al.
(författare)
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Intratumoral administration of pro-inflammatory allogeneic dendritic cells improved the anti-turnor response of systemic anti-CTLA-4 treatment via unleashing a T cell-dependent response
- 2022
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Ingår i: Oncoimmunology. - : Informa UK Limited. - 2162-4011 .- 2162-402X. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- Immune checkpoint inhibitors (ICIs) have revolutionized the oncology field. However, a significant number of patients do not respond, at least partly due to the lack of preexisting anti-tumor T-cell immunity. Therefore, it is emergent to add an immune-priming step to improve efficacy. Here, we report a combined approach consisting of intratumoral administration of pro-inflammatory allogeneic dendritic cells (AlloDCs) and systemic treatment with alpha CTLA-4 that can drastically improve the anti-tumor efficacy compared to alpha CTLA-4 monotherapy. When evaluated in mice with large established CT-26 tumors, monotherapy with alpha CTLA-4 neither delayed tumor progression nor improved mice survival. However, combination treatment of AlloDCs and alpha CTLA-4 drastically improved the effectiveness, with 70% of mice being cured. This effect was T cell-dependent, and all survived mice rejected a subsequent tumor re-challenge. Further investigation revealed an immune-inflamed tumor microenvironment (TME) in the combination treatment group characterized by enhanced infiltration of activated antigen-presenting endogenous DCs and CD8(+) T cells with a tissue-resident memory (T-RM) phenotype (CD49a(+)CD103(+)). This correlated with elevated levels of tumor-specific CD39(+)CD103(+)CD8(+) T cells in the tumor and "tumor-matching" NKG2D(+)CD39(+)CX3CR1(+)CD8(+) T cells in peripheral blood. Moreover, splenocytes from mice in the combination treatment group secreted significantly higher IFN-gamma upon stimulation with the peptide from the endogenous CT-26 retroviral gp70 (model neoantigen), confirming the induction of a tumor-specific CD8(+) T-cell response. Taken together, these data indicate a strong anti-tumor synergy between AlloDCs and alpha CTLA-4 that warrant further clinical investigation with the corresponding human AlloDC product (ilixadencel) for patients receiving alpha CTLA-4 therapy.
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