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Fractional Laser Releases Tumor-Associated Antigens in Poorly Immunogenic Tumor and Induces Systemic Immunity.

ABSTRACT: Currently ablative fractional photothermolysis (aFP) with CO₂ laser is used for a wide variety of dermatological indications. This study presents and discusses the utility of aFP for treating oncological indications. We used a fractional CO₂ laser and anti-PD-1 inhibitor to treat a tumor established unilaterally by the CT26 wild type (CT26WT) colon carcinoma cell line. Inoculated tumors grew significantly slower in aFP-treated groups (aFP and aFP?+?anti-PD-1 groups) and complete remission was observed in the aFP-treated groups. Flow cytometric analysis showed aFP treatment elicited an increase of CD3+, CD4+, CD8+ vand epitope specific CD8+ T cells. Moreover, the ratio of CD8+ T cells to Treg increased in the aFP-treated groups. Additionally, we established a bilateral CT26WT-inoculated mouse model, treating tumors on one-side and observing both tumors. Interestingly, tumors grew significantly slower in the aFP?+?anti-PD-1 groups and complete remission was observed for tumors on both aFP-treated and untreated sides. This study has demonstrated a potential role of aFP treatments in oncology.

SUBMITTER: Kawakubo M

PROVIDER: S-EPMC5630620 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Fractional Laser Releases Tumor-Associated Antigens in Poorly Immunogenic Tumor and Induces Systemic Immunity.

Kawakubo Masayoshi M Cunningham Trevor J TJ Demehri Shadmehr S Manstein Dieter D

Scientific reports 20171006 1

Currently ablative fractional photothermolysis (aFP) with CO<sub>2</sub> laser is used for a wide variety of dermatological indications. This study presents and discusses the utility of aFP for treating oncological indications. We used a fractional CO<sub>2</sub> laser and anti-PD-1 inhibitor to treat a tumor established unilaterally by the CT26 wild type (CT26WT) colon carcinoma cell line. Inoculated tumors grew significantly slower in aFP-treated groups (aFP and aFP + anti-PD-1 groups) and com ...[more]

PMID: 28986576

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Project description:Dendritic cells (DCs) are a promising therapeutic target in cancer immunotherapy given their ability to prime antigen-specific T cells, and initiate antitumor immune response. A major obstacle for DC-based immunotherapy is the difficulty to obtain a sufficient number of functional DCs. Theoretically, this limitation can be overcome by using induced pluripotent stem cells (iPSCs); however, therapeutic strategies to engage iPSC-derived DCs (iPSC-DCs) into cancer immunotherapy remain to be elucidated. Accumulating evidence showing that induction of tumor-residing DCs enhances immunomodulatory effect of radiotherapy (RT) prompted us to investigate antitumor efficacy of combining intratumoral administration of iPSC-DCs with local RT. Mouse iPSCs were differentiated to iPSC-DCs on OP9 stromal cells expressing the notch ligand delta-like 1 in the presence of granulocyte macrophage colony-stimulating factor. Phenotype and the capacities of iPSC-DCs to traffic tumor-draining lymph nodes (TdLNs) and prime antigen-specific T cells were evaluated by flow cytometry and imaging flow cytometry. Antitumor efficacy of intratumoral injection of iPSC-DCs and RT was tested in syngeneic orthotopic mouse tumor models resistant to anti-PD-1 ligand 1 (PD-L1) therapy. Mouse iPSC-DCs phenotypically resembled conventional type 2 DCs, and had a capacity to promote activation, proliferation and effector differentiation of antigen-specific CD8+ T cells in the presence of the cognate antigen in vitro. Combination of in situ administration of iPSC-DCs and RT facilitated the priming of tumor-specific CD8+ T cells, and synergistically delayed the growth of not only the treated tumor but also the distant non-irradiated tumors. Mechanistically, RT enhanced trafficking of intratumorally injected iPSC-DCs to the TdLN, upregulated CD40 expression, and increased the frequency of DC/CD8+ T cell aggregates. Phenotypic analysis of tumor-infiltrating CD8+ T cells and myeloid cells revealed an increase of stem-like Slamf6+ TIM3- CD8+ T cells and PD-L1 expression in tumor-associated macrophages and DCs. Consequently, combined therapy rendered poorly immunogenic tumors responsive to anti-PD-L1 therapy along with the development of tumor-specific immunological memory. Our findings illustrate the translational potential of iPSC-DCs, and identify the therapeutic efficacy of a combinatorial platform to engage them for overcoming resistance to anti-PD-L1 therapy in poorly immunogenic tumors.

Dataset Information

Fractional Laser Releases Tumor-Associated Antigens in Poorly Immunogenic Tumor and Induces Systemic Immunity.

Publications

Fractional Laser Releases Tumor-Associated Antigens in Poorly Immunogenic Tumor and Induces Systemic Immunity.

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