CC BY
3DOI 10.24412/cl-37136-2023-1-39-46
RESEARCH ON SYNERGISTIC IMMUNOTHERAPY TRIGGERED BY PHOTOTHERAPY
WEN SONG, FEIFAN ZHOU
School of Biomedical Engineering, Hainan University songwen@hainanu.edu.cn
ABSTRACT
In recent years, an increasing number of patients with advanced cancer have benefited from immunotherapy (1). However, attributing to the heterogeneity of tumors and the limited efficacy of these therapeutic modalities in eliminating solid tumors, the proportion of benefited cancer patients is less than 15%. Moreover, some modalities of immunotherapy could also cause side effects mainly due to insufficient targeting, which could sometimes be even fatal to patients. Therefore, finding efficient modalities of immunotherapy is of great importance.
Phototherapy, including photodynamic therapy and photothermal therapy, have gained great popularity among researchers (2). In particularly, phototherapy has a very high precision therapeutic effect on tumor regions due to its high spatio-temporal selectivity (3), while the toxic side effects on normal tissues are extremely limited. Therefore, is it possible to develop a synergistic immunotherapy triggered by phototherapy to achieve precise immunotherapy on tumors?
In this presentation, I will give an introduction to our recent works, which are focused on the development of strategies on synergistic immunotherapy triggered by phototherapy for tumor therapy.
In the first part (4), we designed and synthesized an amphiphilic chimeric peptide P-1MT to construct a strategy of immunotherapy triggered by photodynamic therapy. By designing the certain amino acid sequence, we combined 1-methyltryptophan (1-MT), a small molecule inhibitor of IDO pathway, with Asp-Glu-Val-Asp (DEVD), a caspase-responsive peptide sequence. Photodynamic therapy by protoporphyrin (PpIX) could induce tumor cell apoptosis and activate the expression of Caspases-3 to achieve precise release of 1-MT in tumor area, thereby inhibiting the IDO downstream pathway and ultimately achieving eradication of both primary and lung metastasis tumor.
Figure: Phototherapy-triggered immunotherapy for the application in cancer treatment
In the second part (5), we designed and developed a photoactivated immunotherapy nanoplatform (Apt@AuNC) to construct a strategy of immunotherapy triggered by photothermal therapy. Gold nanocage (AuNC) was chosen as the photothermal material of the nanoplatform. A single-stranded DNA with a thiol modification at the 5'-terminus, 5'-SH-T-TTT-TTT-TTT-T-GTA-GTG-CAG-GGA-3', was attached to the surface of AuNC through gold-sulfur bonds. The aptamer Apt that could target PD-1 protein, 5'-FAM-GTA-CAG-TTC-CCG-TCC-CTG-CAC-TAC-A-3', is connected to the outermost layer of AuNC through the principle of complementary base pairing. At the same time, the Apt was modified with a fluorescent molecular FAM at the 5'-terminus. The fluorescence of FAM was quenched initially due to the localized surface plasmon resonance (LSPR) of AuNC. When illuminated, the thermal unwinding reaction of DNA double strands was activated via the heat generated by AuNC. Simultaneously, the aptamer Apt was released from the surface of Apt@AuNC and the fluorescence of FAM was recovered. Then, Apt combined with PD-1 protein on the surface of T lymphocytes to activate the immune system in tumor area, while the AuNC continued to kill tumor cells through photothermal effect.
In the third part (6), we constructed a nanoplatform (M@P@HA) to develop a strategy with amplification of the activation of STING pathway via photodynamic therapy to achieve activation of the innate immune system. Under light irradiation, the generated reactive oxygen species (ROS) disrupt the cellular redox homeostasis to lead cytoplasm leakage of damaged mitochondrial dsDNA which is the initiator of STING signal. Simultaneously, the decomposition of hollow mesoporous manganese dioxide could significantly increase the activity of related protein of STING signal to further amplify STING signal of tumor cells. Subsequently, the STING signal of tumor associated macrophages (TAM) is also activated by capturing dsDNA and Mn2+ escaped from tumor cells, so as to enhance innate immunity and ultimately strengthen the efficacy of anti-tumor therapy.
In summary, phototherapy-triggered synergistic immunotherapy strategy will provide new ideas for the clinical application for antitumor precision immunotherapy.
REFERENCES
[1] Kalbasi, A.; Ribas, A. Tumour-Intrinsic Resistance to Immune Checkpoint Blockade. Nat. Rev. Immunol. 2020, 20, 25-39.
[2] Xiong, J.; Chu, J. C. H.; Fong, W. P.; Wong, C. T. T.; Ng, D. K. P. Specific Activation of Photosensitizer with Extrinsic Enzyme for Precisive Photodynamic Therapy. J. Am. Chem. Soc. 2022, 144,10647-10658.
[3] Chen, A.; Yang, F.; Kuang, J.; Xiong, Y.; Mi, B. B.; Zhou, Y.; Hu, J. J.; Song, S. J.; Wan, T.; Wan, Z. Z.; Huang, H. Y.; Li, X. R.; Song, W.; Qiu, W. X. A Versatile Nanoplatform for Broad-Spectrum Immunotherapy by Reversing the Tumor Microenvironment. ACS Appl. Mater. Interfaces 2021, 13, 45335-45345.
[4] Song, W.; Kuang, J.; Li, C. X.; Zhang, M.; Zheng, D.; Zeng, X.; Liu, C.; Zhang, X. Z., Enhanced Immunotherapy Based on Photodynamic Therapy for Both Primary and Lung Metastasis Tumor Eradication. ACS Nano 2018, 12, 1978-1989.
[5] Song, W.; Hu, J.-J.; Song, S.-J.; Xu, Y.; Yang, H.; Yang, F.; Zhou, Y.; Yu, T.; Qiu, W.-X., Aptamer-Gold Nanocage Composite for Photoactivated Immunotherapy. ACS Appl. Mater. Interfaces 2022. 14, 42931-42939.
[6] Song, W.; Song, S. J.; kuang, j.; Yang, H.; Yu, T.; Yang, F.; Wan, T.; Xu, Y.; Wei, S. T.; Li, M. X.; Xiong, Y.; Zhou, Y.; Qiu, W. X.. Activating Innate Immunity by a STING Signal Amplifier for Local and Systemic Immunotherapy. ACS Nano 2022. 16, 15977-15993.
