Progress on basic research and clinical application of hyperthermia combined with immune checkpoint inhibitors
Liu Pengyuan1, Wu Yajun2, Wu Zhibing3
1The Second Clinical Medical College of Zhejiang Chinese Medical University,Hangzhou 310053,China; 2TCM Dispensary, Affiliated Zhejiang Hospital of Zhejiang University School of Medicine, Hangzhou 310030,China; 3Department of Oncology, Affiliated Zhejiang Hospital of Zhejiang University School of Medicine, Hangzhou 310030,China
Abstract：Malignant tumor is a persistent disease that perplexes public health. Traditional treatment appears ineffective for patients with advanced metastasis. In recent years, immune checkpoint inhibitor therapy has developed rapidly and has great potential, but the overall clinical efficiency is still low. Carcinoma changes the tumor microenvironment through various mechanisms, resulting in immune resistance, which greatly reduces the efficacy of immune checkpoint inhibitors. Hyperthermia can not only play the anti-tumor advantage of thermal effect, but also play a direct and indirect immune sensitization effect through a variety of ways, transforming"cold tumor" into"hot tumor", to enhance the impact of immune checkpoint inhibitors in many patterns. Numerous basic experiments have proved that hyperthermia combined with immune checkpoint inhibitors has achieved a classy impression in mice. Presently, some ongoing clinical trials of hyperthermia combined with immune checkpoint inhibitors have gained promising progress. In this paper, the merits of combination therapy were analyzed from three aspects:immune checkpoint inhibitors, hyperthermia, hyperthermia combined with immune checkpoint inhibitors, and the future research directions of hyperthermia combined with immune checkpoint inhibitors were prospected.
Liu Pengyuan,Wu Yajun,Wu Zhibing. Progress on basic research and clinical application of hyperthermia combined with immune checkpoint inhibitors[J]. Chinese Journal of Radiation Oncology, 2022, 31(5): 483-487.
[1] International Agency for Research on Cancer (IARC). World Cancer Report:Cancer Research for Cancer Prevention World Cancer Reports[M]. WHO, 2020. [2] Das S, Johnson DB. Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors[J]. J Immunother Cancer, 2019, 7(1):306. DOI:10.1186/s40425-019-0805-8. [3] Wang S, He Z, Wang X, et al. Antigen presentation and tumor immunogenicity in cancer immunotherapy response prediction[J]. Elife, 2019, 8:e49020. DOI:10.7554/eLife.49020. [4] Shchors K, Evan G. Tumor angiogenesis:cause or consequence of cancer?[J]. Cancer Res, 2007, 67(15):7059-7061. DOI:10.1158/0008-5472.CAN-07-2053. [5] Roca C, Primo L, Valdembri D, et al. Hyperthermia inhibits angiogenesis by a plasminogen activator inhibitor 1-dependent mechanism[J]. Cancer Res, 2003, 63(7):1500-1507. [6] Toraya-Brown S, Fiering S. Local tumour hyperthermia as immunotherapy for metastatic cancer[J]. Int J Hyperthermia, 2014, 30(8):531-539. DOI:10.3109/02656736.2014.968640. [7] Zhu J, Zhang Y, Zhang A, et al. Cryo-thermal therapy elicits potent anti-tumor immunity by inducing extracellular Hsp70-dependent MDSC differentiation[J]. Sci Rep, 2016, 6:27136. DOI:10.1038/srep27136. [8] Mahmood J, Shukla HD, Soman S, et al. Immunotherapy, radiotherapy, and hyperthermia:A combined therapeutic approach in pancreatic cancer treatment[J]. Cancers (Basel), 2018, 10(12) DOI:10.3390/cancers10120469. [9] Singh IS, Hasday JD. Fever, hyperthermia and the heat shock response[J]. Int J Hyperthermia, 2013, 29(5):423-435. DOI:10.3109/02656736.2013.808766. [10] Knippertz I, Stein MF, Dörrie J, et al. Mild hyperthermia enhances human monocyte-derived dendritic cell functions and offers potential for applications in vaccination strategies[J]. Int J Hyperthermia, 2011, 27(6):591-603. DOI:10.3109/02656736.2011.589234. [11] Morlé A, Garrido C, Micheau O. Hyperthermia restores apoptosis induced by death receptors through aggregation-induced c-FLIP cytosolic depletion[J]. Cell Death Dis, 2015, 6(2):e1633. DOI:10.1038/cddis.2015.12. [12] Klostergaard J, Leroux ME, Auzenne E, et al. Hyperthermia engages the intrinsic apoptotic pathway by enhancing upstream caspase activation to overcome apoptotic resistance in MCF-7 breast adenocarcinoma cells[J]. J Cell Biochem, 2006, 98(2):356-369. DOI:10.1002/jcb.20729. [13] Lefor AT, Foster CE 3rd, Sartor W, et al. Hyperthermia increases intercellular adhesion molecule-1 expression and lymphocyte adhesion to endothelial cells[J]. Surgery, 1994, 116(2):214-220;discussion 220-221. [14] Baronzio G, Gramaglia A, Fiorentini G. Hyperthermia and immunity. A brief overview[J]. in vivo, 2006, 20(6A):689-695. [15] Mace TA, Zhong L, Kokolus KM, et al. Effector CD+8 T cell IFN-γ production and cytotoxicity are enhanced by mild hyperthermia[J]. Int J Hyperthermia, 2012, 28(1):9-18. DOI:10.3109/02656736.2011.616182. [16] Cippitelli M, Fionda C, Di Bona D, et al. Hyperthermia enhances CD95-ligand gene expression in T lymphocytes[J]. J Immunol, 2005, 174(1):223-232. DOI:10.4049/jimmunol.174.1.223. [17] Shi L, Chen L, Wu C, et al. PD-1 blockade boosts radiofrequency ablation-elicited adaptive immune responses against tumor[J]. Clin Cancer Res, 2016, 22(5):1173-1184. DOI:10.1158/1078-0432.CCR-15-1352. [18] Cao G, Wang J, Zheng X, et al. Tumor therapeutics work as stress inducers to enhance tumor sensitivity to natural killer (NK) cell cytolysis by up-regulating NKp30 ligand B7-H6[J]. J Biol Chem, 2015, 290(50):29964-29973. DOI:10.1074/jbc.M115.674010. [19] Kubista B, Trieb K, Blahovec H, et al. Hyperthermia increases the susceptibility of chondro-and osteosarcoma cells to natural killer cell-mediated lysis[J]. Anticancer Res, 2002, 22(2A):789-792. [20] Guo D, Chen Y, Wang S, et al. Exosomes from heat-stressed tumour cells inhibit tumour growth by converting regulatory T cells to Th17 cells via IL-6[J]. Immunology, 2018, 154(1):132-143. DOI:10.1111/imm.12874. [21] Han X, Wang R, Xu J, et al. In situ thermal ablation of tumors in combination with nano-adjuvant and immune checkpoint blockade to inhibit cancer metastasis and recurrence[J]. Biomaterials, 2019, 224:119490. DOI:10.1016/j.biomaterials.2019.119490. [22] Pan J, Hu P, Guo Y, et al. Combined magnetic hyperthermia and immune therapy for primary and metastatic tumor treatments[J]. ACS Nano, 2020, 14(1):1033-1044. DOI:10.1021/acsnano.9b08550. [23] Hu C, Cai L, Liu S, et al. Copper-doped nanoscale covalent organic polymer for augmented photo/chemodynamic synergistic therapy and immunotherapy[J]. Bioconjug Chem, 2020, 31(6):1661-1670. DOI:10.1021/acs.bioconjchem.0c00209. [24] Huang L, Li Y, Du Y, et al. Mild photothermal therapy potentiates anti-PD-L1 treatment for immunologically cold tumors via an all-in-one and all-in-control strategy[J]. Nat Commun, 2019, 10(1):4871. DOI:10.1038/s41467-019-12771-9. [25] Oei AL, Korangath P, Mulka K, et al. Enhancing the abscopal effect of radiation and immune checkpoint inhibitor therapies with magnetic nanoparticle hyperthermia in a model of metastatic breast cancer[J]. Int J Hyperthermia, 2019, 36(sup1):47-63. DOI:10.1080/02656736.2019.1685686. [26] Duffy AG, Ulahannan SV, Makorova-Rusher O, et al. Tremelimumab in combination with ablation in patients with advanced hepatocellular carcinoma[J]. J Hepatol, 2017, 66(3):545-551. DOI:10.1016/j.jhep.2016.10.029. [27] Kleef R, Moss R, Szasz AM, et al. Complete clinical remission of stage Ⅳ triple-negative breast cancer lung metastasis aDministering low-dose immune checkpoint blockade in combination with hyperthermia and interleukin-2[J]. Integr Cancer Ther, 2018, 17(4):1297-1303. DOI:10.1177/1534735418794867. [28] Wei Z, Yang X, Ye X, et al. Camrelizumab combined with microwave ablation improves the objective response rate in advanced non-small cell lung cancer[J]. J Cancer Res Ther, 2019, 15(7):1629-1634. DOI:10.4103/jcrt.JCRT_990_19. [29] Chen H, Luan X, Paholak HJ, et al. Depleting tumor-associated Tregs via nanoparticle-mediated hyperthermia to enhance anti-CTLA-4 immunotherapy[J]. Nanomedicine (Lond), 2020, 15(1):77-92. DOI:10.2217/nnm-2019-0190. [30] Shi L, Wang J, Ding N, et al. Inflammation induced by incomplete radiofrequency ablation accelerates tumor progression and hinders PD-1 immunotherapy[J]. Nat Commun, 2019, 10(1):5421. DOI:10.1038/s41467-019-13204-3. [31] Choi J, Lee SY. Clinical characteristics and treatment of immune-related adverse events of immune checkpoint inhibitors[J]. Immune Netw, 2020, 20(1):e9. DOI:10.4110/in.2020.20.e9. [32] De Velasco G, Je Y, Bossé D, et al. Comprehensive meta-analysis of key immune-related adverse events from CTLA-4 and PD-1/PD-l1 inhibitors in cancer patients[J]. Cancer Immunol Res, 2017, 5(4):312-318. DOI:10.1158/2326-6066.CIR-16-0237. [33] Martins F, Sofiya L, Sykiotis GP, et al. Adverse effects of immune-checkpoint inhibitors:epidemiology, management and surveillance[J]. Nat Rev Clin Oncol, 2019, 16(9):563-580. DOI:10.1038/s41571-019-0218-0. [34] Notter M, Piazena H, Vaupel P. Hypofractionated re-irradiation of large-sized recurrent breast cancer with thermography-controlled, contact-free water-filtered infra-red-A hyperthermia:a retrospective study of 73 patients[J]. Int J Hyperthermia, 2017, 33(2):227-236. DOI:10.1080/02656736.2016.1235731. [35] Wang C, Ye Y, Hochu GM, et al. Enhanced cancer immunotherapy by microneedle patch-assisted delivery of anti-PD1 antibody[J]. Nano Lett, 2016, 16(4):2334-2340. DOI:10.1021/acs.nanolett.5b05030. [36] Han X, Wang R, Xu J, et al. In situ thermal ablation of tumors in combination with nano-adjuvant and immune checkpoint blockade to inhibit cancer metastasis and recurrence[J]. Biomaterials, 2019, 224:119490. DOI:10.1016/j.biomaterials.2019.119490. [37] Dong X, Cheng R, Zhu S, et al. A heterojunction structured WO (2.9)-WSe (2) nanoradiosensitizer increases local tumor ablation and checkpoint blockade immunotherapy upon low radiation dose[J]. ACS Nano, 2020, 14(5):5400-5416. DOI:10.1021/acsnano.9b08962.
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