TLR9 agonist enhances radiofrequency ablation-induced CTL responses, leading to the potent inhibition of primary tumor growth and lung metastasis 

Abstract

Radiofrequency ablation (RFA) is the most common approach to thermal ablation for cancer therapy. Unfortunately, its efficacy is limited by incomplete ablation, and further optimization of RFA is required. Here, we demonstrate that incubation at 65°C triggers more EG7 tumor cell death by necrosis than treatment at 45°C, and the 65°C-treated cells are more effective at inducing antigenspecific CD8 + cytotoxic T lymphocyte (CTL) responses after injection in mice than the 45°C-treated ones. Dendritic cells (DCs) that phagocytose 65°C-treated EG7 cells become mature with upregulated MHCII and CD80 expression and are capable of efficiently inducing effector CTLs in mouse tumor models. RFA (65°C) therapy of EG7 tumors induces large areas of tumor necrosis and stimulates CTL responses. This leads to complete regression of small (~100 mm 3) tumors but fails to suppress the growth of larger (~350 mm 3) tumors. The administration of the Toll-like receptor-9 (TLR9) agonist unmethylated cytosine-phosphorothioate-guanine oligonucleotide (CpG) to DCs phagocytosing 65°C-treated EG7 cells enhances the expression of MHCII and CD40 on DCs as well as DC-induced stimulation of CTL responses. Importantly, the intratumoral administration of CpG following RFA also increases the frequencies of tumor-associated immunogenic CD11b − CD11c + CD103 + DC2 and CD11b + F4/80 + MHCII + M1 macrophages and increases CD4 + and CD8 + T-cell tumor infiltration, leading to enhanced CD4 + T cell-dependent CTL responses and potent inhibition of primary RFA-treated or distant untreated tumor growth as well as tumor lung metastasis in mice bearing larger tumors. Overall, our data indicate that CpG administration, which enhances RFA-induced CTL responses and ultimately potentiates the inhibition of primary tumor growth and lung metastasis, is a promising strategy for improving RFA treatment, which may assist in optimizing this important cancer therapy.

NIR-light-mediated spatially selective triggering of anti-tumor immunity via upconversion nanoparticle-based immunodevices

“…Mice were intravenously injected with different samples every other day for three times. Tumors were immediately disaggregated into single-cell suspensions (SCSs) 59 . Cells were stained with specific antibodies for analysis of CD4 + T, CD8 + T cells, and Tregs in tumors using Gallios Flow cytometry (Beckman Coulter, USA).…”

<p>Resistance Mechanism of PD-1/PD-L1 Blockade in the Cancer-Immunity Cycle</p>

“…DCs, as the most potent APCs currently discovered, are capable of inducing specific cytotoxic T lymphocytes (CTLs) production. 18 However, DCs often do not function efficiently in the tumor environment. The tumor microenvironment can affect the distribution, differentiation, and maturation of DCs.…”

Unleashing Tumour-Dendritic Cells to Fight Cancer by Tackling Their Three A’s: Abundance, Activation and Antigen-Delivery

“…TADCs that phagocytosed 65 °C-treated EG7 cells expressed higher levels of MHCII and CD80 and were able to induce CTL responses, leading to the regression of small tumours (approx. 100 mm 3 ) [87]. DC maturation was more enhanced after administration of CpG following RFA, resulting in the control of larger tumours and metastasis formation [87].…”

“…100 mm 3 ) [87]. DC maturation was more enhanced after administration of CpG following RFA, resulting in the control of larger tumours and metastasis formation [87]. Combined radiotherapy, intratumoural CpG and PD-1 blockade reduced tumour growth and improved host survival using the murine lung cancer model LLC [88].…”

“…After cryo-ablation of the primary B16 melanoma tumour, mice were re-challenged with B16 cells. 71% and 79% of mice treated with either of the two saponin-based adjuvants during the primary tumour ablation survived the secondary challenge, compared to 24% of mice that received no adjuvant with the cryo-ablation [87].…”