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Supramolecular Photothermal Nanomedicine Mediated Distant Tumor Inhibition via PD-1 and TIM-3 Blockage.

ABSTRACT: Supramolecular nanoparticles for photothermal therapy (PTT) have shown promising therapeutic efficacy in the primary tumor and great potential for turning the whole-body immune microenvironment from "cold" to "hot," which allows for the simultaneous treatment of the primary tumor and the metastatic site. In this work, we develop a liposome-based PTT nanoparticle through the self-assembly of FDA-approved intravenous injectable lipids and a photothermal agent, indocyanine green (ICG). The obtained ICG-liposome shows long-term storage stability, high ICG encapsulation efficiency (>95%), and enhanced near-infrared (NIR) light-triggered photothermal reaction both in vitro and in vivo. The ICG-liposome efficiently eradicated the primary tumor upon laser irradiation in two colon cancer animal models (CT26 and MC38) and promoted the infiltration of CD8 T cells to distant tumors. However, PTT from ICG-liposome shows only a minimal effect on the inhibition of distant tumor growth in long-term monitoring, predicting other immunosuppressive mechanisms that exist in the distant tumor. By immune-profiling of the tumor microenvironment, we find that the distant tumor growth after PTT highly correlates to compensatory upregulation of immune checkpoint biomarkers, including program death-1 (PD-1), T-cell immunoglobulin, and mucin domain-containing protein 3 (TIM-3), in tumor-infiltrating CD8 T cells. Based on this mechanism, we combine dual PD-1 and TIM-3 blockade with PTT in an MC38 tumor model. This combo successfully clears the primary tumor, generates a systemic immune response, and inhibits the growth of the distant tumor. The ICG-liposome-combined PD-1/TIM-3 blockade strategy sheds light on the future clinical use of supramolecular PTT for cancer immunotherapy.

SUBMITTER: Huang TY

PROVIDER: S-EPMC7034522 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Supramolecular Photothermal Nanomedicine Mediated Distant Tumor Inhibition via PD-1 and TIM-3 Blockage.

Huang Tong-Yi TY Huang Guang-Liang GL Zhang Chun-Yang CY Zhuang Bo-Wen BW Liu Bao-Xian BX Su Li-Ya LY Ye Jie-Yi JY Xu Ming M Kuang Ming M Xie Xiao-Yan XY

Frontiers in chemistry 20200214

Supramolecular nanoparticles for photothermal therapy (PTT) have shown promising therapeutic efficacy in the primary tumor and great potential for turning the whole-body immune microenvironment from "cold" to "hot," which allows for the simultaneous treatment of the primary tumor and the metastatic site. In this work, we develop a liposome-based PTT nanoparticle through the self-assembly of FDA-approved intravenous injectable lipids and a photothermal agent, indocyanine green (ICG). The obtained ...[more]

PMID: 32117862

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Project description:In situ vaccination is an emerging cancer treatment strategy that uses local therapies to stimulate a systemic antitumor immune response. We previously reported an in situ vaccination effect when combining radiation (RT) with intratumor (IT) injection of tumor-specific immunocytokine (IC), a fusion of tumor-specific antibody and IL2 cytokine. In mice bearing two tumors, we initially hypothesized that delivering RT plus IT-IC to the "primary" tumor would induce a systemic antitumor response causing regression of the "secondary" tumor. To test this, mice bearing one or two syngeneic murine tumors of B78 melanoma and/or Panc02 pancreatic cancer were treated with combined external beam RT and IT-IC to the designated "primary" tumor only. Primary and secondary tumor response as well as animal survival were monitored. Immunohistochemistry and quantitative real-time PCR were used to quantify tumor infiltration with regulatory T cells (Treg). Transgenic "DEREG" mice or IgG2a anti-CTLA-4 were used to transiently deplete tumor Tregs. Contrary to our initial hypothesis, we observed that the presence of an untreated secondary tumor antagonized the therapeutic effect of RT + IT-IC delivered to the primary tumor. We observed reciprocal tumor specificity for this effect, which was circumvented if all tumors received RT or by transient depletion of Tregs. Primary tumor treatment with RT + IT-IC together with systemic administration of Treg-depleting anti-CTLA-4 resulted in a renewed in situ vaccination effect. Our findings show that untreated tumors can exert a tumor-specific, Treg-dependent, suppressive effect on the efficacy of in situ vaccination and demonstrate clinically viable approaches to overcome this effect. Untreated tumor sites antagonize the systemic and local antitumor immune response to an in situ vaccination regimen. This effect is radiation sensitive and may be mediated by tumor-specific regulatory T cells harbored in the untreated tumor sites. Cancer Immunol Res; 6(7); 825-34. ©2018 AACR.

Dataset Information

Supramolecular Photothermal Nanomedicine Mediated Distant Tumor Inhibition via PD-1 and TIM-3 Blockage.

Publications

Supramolecular Photothermal Nanomedicine Mediated Distant Tumor Inhibition via PD-1 and TIM-3 Blockage.

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