Date Published: February 26, 2018
Publisher: John Wiley and Sons Inc.
Author(s): Jinrong Peng, Yao Xiao, Wenting Li, Qian Yang, Liwei Tan, Yanpeng Jia, Ying Qu, Zhiyong Qian.
The therapeutic outcome of photothermal therapy (PTT) remains impeded by the transparent depth of light. Combining PTT with immunotherapy provides strategies to solve this problem. Regulating metabolism‐related enzymes is a promising strategy to stimulate immune response. Here, a nanosystem (NLG919/IR780 micelles) with the properties of photothermal conversion and regulation of the tryptophan metabolic pathway is used to suppress the growth of the tumor margin beyond effective PTT and promote tumor PTT and immunotherapy. It is revealed that mild heat treatment promotes the growth of the tumor margin beyond effective PTT for the upregulation of heat shock protein (HSP), indoleamine 2,3‐dioxygenase (IDO), and programmed death‐ligand 1 (PD‐L1). The NLG919/IR780 micelles can effectively inhibit the activity of IDO but do not affect the level of IDO expression. NLG919/IR780 micelles can effectively accumulate in the tumor and can migrate to lymph nodes and the lymphatic system. In vivo antitumor studies reveal that NLG919/IR780 micelles effectively suppress the growth of tumor margin following PTT in primary tumors. NLG919/IR780 micelle‐mediated PTT and IDO inhibition further stimulate the activation of T lymphocytes, inhibiting the growth of distal tumors (abscopal effect). The results demonstrate that the NLG919/IR780 micelles combine PTT and immunotherapy and suppress the tumor margin as well as distal tumor growth post photothermal therapy.
The emergence of nanomedicines provides an alternative strategy for the delivery of therapeutic agents.1 The ongoing development of nanoparticles not only improves the targeting and bioavailability of drugs and develops new therapeutic methods, such as photothermal therapy and nanovaccines, but also provides a suitable carrier for the realization of combination therapy.2, 3, 4, 5, 6, 7 Moreover, some nanoparticle‐based systems can strengthen the immune response in tumor immunotherapy, which has attracted much attention.8, 9, 10, 11
In summary, we first evaluated the effect of mild heating on the growth rate of tumor cells in vitro and in vivo. We observed that the tumor margin beyond effective PTT proliferated faster than the untreated tumor due to the upregulation of HSP, IDO, PD‐L1, etc. To efficiently inhibit the growth of the localized tumor and stimulate the host to generate an immune response to suppress the growth of the tumor margin beyond effective PTT and the distal tumor, we have developed a nanomedicine containing NIR photosensitizer (IR780) and IDO inhibitor (NLG919) to realize tumor photothermal therapy and immunotherapy. Through in vitro cellular assay, we confirmed that the NLG919/IR780 micelles can inhibit the activity of IDO but do not suppress the IDO expression. When the treatment was combined with PTT, the tumor cell growth was efficiently inhibited in vitro and in vivo. We also proved that the NLG919/IR780 micelles can accumulate in the tumor site via passive targeting and migrate to the lymphatic system to enter the lymphatic circulation. By investigating the antitumor performance in vivo, we found that the NLG919/IR780‐micelle‐mediated PTT and immunotherapy efficiently inhibited the primary tumor, suppressed the growth of secondary tumor, and increased the infiltrated T cells in tumor tissue, favoring the differentiation of T cells to CD8+ T cells. Combined with the suppression of Treg activity, NLG919/IR780‐micelle‐mediated PTT and immunotherapy showed a therapeutic outcome. The results demonstrated that the NLG/IR780 micelles enable the suppression of the tumor margin beyond effective PTT and strengthen the immune response to inhibit the distal tumor.
Material: Methoxy poly (ethylene glycol) (MPEG‐OH, Mn = 2000), stannous octoate (Sn(Oct)2), ∂‐lipoic acid, tetradecanol, pentadecanol, hexadecanol, and ɛ‐caprolatone were purchased from Sigma‐Aldrich (Saint Louis, USA). Photosensitizer IR780 was purchased from Sigma‐Aldrich. IDO inhibitor NLG919 was purchased from Selleck. CD3‐FITC monoclonal antibody (catalog: 11‐0032‐80, clone: 17A2), CD4‐APC monoclonal antibody (catalog: 17‐0041‐82, clone: GK1.5), and CD8a‐PE‐cyanine7 monoclonal antibody (catalog: 25‐0081‐82, clone: 53–6.7) were purchased from Invitrogen (eBioscience, Invitrogen, Thermo Fisher Scientific, Massachusetts, USA). IDO monoclonal antibody (rabbit anti‐IDO, catalog: bs‐15493R), HSP 70 monoclonal antibody, and HSP 90 monoclonal antibody (Monoclonal mouse IgG2B clone# 341320, catalog: MAB3286, R&D) were purchased from Bioss Antibodies and R&D, respectively. 3‐(4,5‐dimethyl‐2‐thiazolyl)‐2,5‐diphenyl‐2H‐tetrazolium bromide (methyl thiazolyltetrazolium) (MTT) were obtained from Sigma‐Aldrich (Saint Louis, USA). The Treg Flow Kit (True‐Nuclear one step staining mouse Treg Flow kit (FOXP3 Alexa FluorR 488/CD25 PE/CD4 PerCP)) was obtained from Biolegend. Dulbecco’s modified Eagle’s medium (DMEM), penicillin‐streptomycin liquid (100X), and fetal bovine serum (FBS) were purchased from HyClone (Logan, USA). Ethanol was purchased from Aladdin (Shanghai, China).
The authors declare no conflict of interest.