Journal Article
. 2022 Feb; 24:429-442.
doi: 10.1016/j.omto.2022.01.003.

Immune priming using DC- and T cell-targeting gene therapy sensitizes both treated and distant B16 tumors to checkpoint inhibition

Jessica Wenthe 1 Sedigheh Naseri 1 Ann-Charlotte Hellström 1 Rafael Moreno 2 Gustav Ullenhag 1 Ramon Alemany 2 Tanja Lövgren 1 Emma Eriksson 1 Angelica Loskog 1 
Affiliations
  • PMID: 35141399
  •     48 References

Abstract

Immune checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, but most tumors show resistance. Resistance is connected to a non-T cell inflamed phenotype partially caused by a lack of functional dendritic cells (DCs) that are crucial for T cell priming. Herein, we investigated whether the adenoviral gene vehicle mLOAd703 carrying both DC- and T cell-activating genes can lead to inflammation in a B16-CD46 model and thereby overcome resistance to checkpoint inhibition therapy. B16-CD46 cells were injected subcutaneously in one or both flanks of immunocompetent C57BL/6J mice. mLOAd703 treatments were given intratumorally alone or in combination with intraperitoneal checkpoint inhibition therapy (anti-PD-1, anti-PD-L1, or anti-TIM-3). Tumor, lymph node, spleen, and serum samples were analyzed for the presence of immune cells and cytokines/chemokines. B16-CD46 tumors were non-inflamed and resistant to checkpoint blockade. In contrast, mLOAd703 treatment led to infiltration of the tumor by CD8+ T cells, natural killer (NK) cells, and CD103+ DCs, accompanied by a systemic increase of pro-inflammatory cytokines interferon γ (IFN-γ), tumor necrosis factor alpha (TNF-α), and interleukin-27 (IL-27). This response was even more pronounced after combining the virus with checkpoint therapy, in particular with anti-PD-L1 and anti-TIM-3, leading to further reduced tumor growth in injected lesions. Moreover, anti-PD-L1 combination also facilitated abscopal responses in non-injected lesions.

Keywords: 4-1BBL; CD40L; PD-1; PD-L1; TIM-3; checkpoint inhibitor; immune checkpoint blockade; oncolytic adenovirus.

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