Возможности тераностики в визуализации микроокружения опухоли и элиминации его иммуносупрессивных компонентов

Одним из перспективных направлений ядерной медицины является тераностика — использование радиофармпрепаратов для диагностики и лечения онкологических заболеваний, особое направление тераностики — иммунотераностика. Цель работы — обобщить возможности тераностики в визуализации микроокружения опухоли и элиминации его иммуносупрессивных компонентов. В статье представлены данные о составе и взаимодействии различных субпопуляций клеток в микроокружении опухоли, а также о роли стволовых опухолевых клеток в его формировании. Описаны дефекты сигнальных путей и потенциальные мишени для тераностики стволовых опухолевых клеток, а также механизм взаимодействия опухоли и иммунной системы в процессе канцерогенеза. Подробно разобраны подходы к оценке типа микроокружения с целью индивидуализации лечения и разработки рационального дизайна клинических исследований тераностических пар. Приведены собственные данные о характере распределения субпопуляций лимфоцитов и супрессорных клеток миелоидного происхождения у пациентов с метастатическими формами различных опухолей. Рассмотрены нюансы создания и использования различных молекул адресной доставки при разработке диагностических и терапевтических радиофармпрепаратов. Описаны наиболее перспективные диагностические и терапевтические изотопы с точки зрения возможности оценки микроокружения и воздействия на него. В статье освещены современные и перспективные методы предварительного таргетинга для снижения токсичности и повышения эффективности тераностики. Рассмотрены также достоинства и недостатки тераностики по сравнению с другими методами системного лечения метастатических форм опухолей. Обозначены пути преодоления недостатков тераностики.

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660

2. Каприн АД, Старинский ВВ, Шахзадова АО, ред. Состояние онкологической помощи населению России в 2019 году. М.: МНИОИ им. П.А. Герцена — филиал ФГБУ «НМИЦ радиологии» Минздрава России; 2020.

3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74. https://doi.org/10.1016/j.cell.2011.02.013

4. Yang L, Lin PS. Mechanisms that drive inflammatory tumor microenvironment, tumor heterogeneity, and metastatic progression. Semin Cancer Biol. 2017;47:185–95. https://doi.org/10.1016/j.semcancer.2017.08.001

5. Dunn GP, Old LJ, Schreiber RD. The three Es of cancer immunoediting. Annu Rev Immunol. 2004;22:329–60. https://doi.org/10.1146/annurev.immunol.22.012703.104803

6. Deshmukh A, Deshpande K, Arfuso F, Newsholme P, Dharmarajan A. Cancer stem cell metabolism: a potential target for cancer therapy. Mol Cancer. 2016;15(1):69. https://doi.org/10.1186/s12943-016-0555-x

7. Buoncervello M, Gabriele L, Toschi E. The Janus face of tumor microenvironment targeted by immunotherapy. Int J Mol Science. 2019;20(17):4320. https://doi.org/10.3390/ijms20174320

8. Jarosz-Biej M, Smolarczyk R, Cihon T, Kulach N. Tumor microenvironment as a «Game Changer» in cancer radiotherapy. Int J Mol Science. 2019;20(13):3212. https://doi.org/10.3390/ijms20133212

9. Schaefer N, Prior JO, Schottelius M. From theranostics to immunotheranostics: the concept. Nucl Med Mol Imag. 2020;54(2):81–5. https://doi.org/10.1007/s13139-020-00639-6

10. Talukdar S, Bhoopathi P, Emdad L, Das S, Sarkar D, Fisher PB. Dormancy and cancer stem cells: an enigma for cancer therapeutic targeting. Adv Cancer Res. 2019; 141:43–84. https://doi.org/10.1016/bs.acr.2018.12.002

11. Masuko K, Masaru K. Precision medicine for human cancers with Notch signaling dysregulation (Review). Int J Mol Med. 2020;45(2):279-97. https://doi.org/10.3892/ijmm.2019.4418

12. Zhang Y, Wang X. Targeting the Wnt/β-catenin signaling pathway in cancer. J Hematol Oncol. 2020;13(1):165. https://doi.org/10.1186/s13045-020-00990-3

13. Garbalo GB, Honorato JR, Farias de Lopes GP, de Sampaio e Spohr TCL. A highlight on Sonic hedgehog pathway. Cell Commun Signal. 2018;16(1):11. https://doi.org/10.1186/s12964-018-0220-7

14. Battle E, Massaque J. Transforming grown factor-β signaling in immunity and cancer. Immunity. 2019;50(4): 924–40. https://doi.org/10.1016/j.immuni.2019.03.024

15. Owen KL, Brockwel NK, Parker BS. JAK-STAT signaling: a double-edged sword of immune regulation and cancer progression. Cancers (Basel). 2019;11(12):2002. https://doi.org/10.3390/cancers11122002

16. Locati M, Curtale G, Mantovani A. Diversity, mechanisms and significance of macrophage plasticity. Annu Rev Pathol. 2020;15:123–47. https://doi.org/10.1146/annurev-pathmechdis-012418-012718

17. Wculek SK, Cueto FJ, Mujal AM, Melero I, Krummel MF, Sancho D. Dendritic cells in cancer immunology and immunotherapy. Nat Rev Immunol. 2020;20(1):7–24. https://doi.org/10.1038/s41577-019-0210-z

18. Lorenzo-Sanz L, Munoz P. Tumor-infiltrating immunosuppressive cells in cancer-cell plasticity, tumor progression and therapy response. Cancer Microenviron. 2019;12(2–3):119–32. https://doi.org/10.1007/s12307-019-00232-2

19. Chiossone L, Dumas PY, Vienne M. Natural killer cells and other innate lymphoid cells in cancer. Nat Rev Immunol. 2018;18(11):671–88. https://doi.org/10.1038/s41577-018-0061-z

20. Ostroumov D, Fekete-Drimusz N, Saborowski M, Kuhnel F, Woller N. CD4 and CD8 T lymphocyte interplay in controlling tumor growth. Cell Mol Life Sci. 2018;75(4):689–713. https://doi.org/10.1007/s00018-017-2686-7

21. Michaud D, Steward CR, Mirlekar B, Pylayeva-Gupta Y. Regulatory B cells in cancer. Immunol Rev. 2021;299(1):74–92. https://doi.org/10.1111/imr.12939

22. Vivier E, Artis D, Colonna M, Diefenbach A, Di Santo JP, Eberl G, et al. Innate lymphoid cells: 10 years on. Cell. 2018;174(5):1054–66. https://doi.org/10.1016/j.cell.2018.07.017

23. Bruchard M, Ghiringhelli F. Deciphering the roles of innate lymphoid cells in cancer. Front Immunol. 2019;10:656. https://doi.org/10.3389/fimmu.2019.00656

24. Tavare R, Escuin-Ordinas H, Mok S, McCracken MN, Zettlitz KA, Salazar FB. An effective immuno-PET imaging method to monitor CD8-dependent responses to immunotherapy. Cancer Res. 2016;76(1):73–82. https://doi.org/10.1158/0008-5472.CAN-15-1707

25. Bensch F, van der Veen EL, Lub-de Hooge MN, Jorritisma-Smit A, Boellaard R, Kok IC, et al. 89 Zr-atezolizumab imaging as a noninvasive approach to assess clinical response to PDL1 blockade in cancer. Nat Med. 2018;24(12):1852–8. https://doi.org/10.1038/s41591-018-0255-8

26. Niemeijer AN, Leung D, Huisman MC, Bahce I, Hoekstra OS, van Dongen GAMS, et al. Whole body PD-1 and PD-L1 positron emission tomography in patients with non-small-cell lung cancer. Nat Commun. 2018;9(1):4664. https://doi.org/10.1038/s41467-018-07131-y

27. Zhang C, Yu X, Gao L, Zhao Y, Lai J, Lu D, et al. Noninvasive imaging of CD206-positive M2 macrophages as an early biomarker for post-chemotherapy tumor relapse and lymph node metastasis. Theranostics. 2017;7(17):4276–88. https://doi.org/10.7150/thno.20999

28. Klug F, Prakash H, Huber PE, Seibel T, Bender N, Halama N, et al. Low-dose irradiation programs macrophage differentiation to an iNOS+/M1 phenotype that orchestrates effective T cell immunotherapy. Cancer Cell. 2013;24(5):589–602. https://doi.org/10.1016/j.ccr.2013.09.014

29. Giesel FL, Kratochwil C, Lindner T, Marschalek MM, Loktev A, Lehnert W, et al. 68 Ga-FAPI PET/CT: biodistribution and preliminary dosimetry estimate of 2 DOTA-containing FAP-targeting agents in patients with various cancers. J Nucl Med. 2019;60(3):386–92. https://doi.org/10.2967/jnumed.118.215913

30. Calais J. FAP: the next billion dollar nuclear theranostics target? J Nucl Med. 2020;61(2):163–5. https://doi.org/10.2967/jnumed.119241232

31. Yu X, Zhang Z, Wang Z, Wu P, Qiu F, Huang J. Prognostic and predictive value of tumor-infiltrating lymphocytes in breast cancer: a systematic review and meta-analysis. Clin Transl Oncol. 2016;18(5):497–506. https://doi.org/10.1007/s12094-015-1391-y

32. Galon J, Mlecnik B, Bindea G, Angell HK, Berger A, Lagorce C, et al. Towards the introduction of the «immunoscore» in the classification of malignant tumors. J Pathol. 2014;232(2):199–209. https://doi.org/10.1002/path.4287

33. Galon J, Bruni D. Approaches to treat immune hot, altered and cold tumors with combination immunotherapies. Nat Rev Drug Disov. 2019;18(3):197–218. https://doi.org/10.1038/s41573-018-0007-y

34. Sgouros G, Bodei L, McDevit MR, Nedrow JR. Radiopharmaceutical therapy in cancer: clinical advances and challenges. Nat Rev Drug Discov. 2020;19(9):589–608. https://doi.org/10.1038/s41573-020-0073-9

35. Fu R, Carrol L, Yahioglu G, Aboagye EO, Miller PW. Antibody fragment and affibody immunoPET imaging agents: radiolabeling strategies and applications. ChemMedChem. 2018;13(23):2466–78. https://doi.org/10.1002/cmdc.201800624

36. Freise AS, Wu AM. In vivo imaging with antibodies and engineered fragments. Mol Immunol. 2015;67(2 Pt A):142–52. https://doi.org/10.1016/j.molimm.2015.04.001

37. Ogasawara A, Tinianow JN, Vanderbilt AN, Gill HS, Yee S, Flores JE, et al. ImmunoPET imaging of phosphatidylserine in pro-apoptotic therapy treated tumor models. Nucl Med Biol. 2013;40(1):15–22. https://doi.org/10.1016/j.nucmedbio.2012.09.001

38. Lütje S, Franssen GM, Sharkey RM, Laverman P, Rossi EA, Goldenberg DM, et al. Anti-CEA antibody fragments labeled with [18 F]AlF for PET imaging of CEA-expressing tumors. Bioconjug Chem. 2014; 25(2):335–41. https://doi.org/10.1021/bc4004926

39. Tavare R, McCracken MN, Zettlitz KA, Knowles SM, Salazar FB, Olafsen T, et al. Engineered antibody fragments for immuno-PET imaging of endogenous CD8+ T cells in vivo. Proc Natl Acad Sci USA. 2014;111(3):1108–13. https://doi.org/10.1073/pnas.1316922111

40. Chakravarty R, Goel S, Valdovinos HF, Hernandez R, Hong H, Nickles RJ, Cai W. Matching the decay half-life with the biological half-life: immunoPET imaging with Sc-labeled Cetuximab Fab fragment. Bioconjug Chem. 2014;25(12):2197–204. https://doi.org/10.1021/bc500415x

41. Tavaré R, Wu WH, Zettlitz KA, Salazar FB, McCabe KE, Marks JD, Wu AM. Enhanced immunoPET of ALCAM-positive colorectal carcinoma using site-specific Cu-DOTA conjugation. Protein Eng Des Sel. 2014;27(10):317–24. https://doi.org/10.1093/protein/gzu030

42. Kim HY, Wang X, Wahlberg B, Edwards WB. Discovery of hapten-specific scFv from a phage display library and applications for HER2-positive tumor imaging. Bioconjug Chem. 2014;25(7):1311–22. https://doi.org/10.1021/bc500173f

43. Bannas P, Well L, Lenz A, Rissiek B, Haag F, Schmid J, et al. In vivo near-infrared fluorescence targeting of T cells: comparison of nanobodies and conventional monoclonal antibodies. Contrast Media Mol Imaging. 2014;9(2):135–42. https://doi.org/10.1002/cmmi.1548

44. Strand J, Varasteh Z, Eriksson O, Abrahmsen L, Orlova A, Tolmachev V, et al. Gallium-68-labeled affibody molecule for PET imaging of PDGFRβ expression in vivo. Mol Pharm. 2014;11(11):3957–64. https://doi.org/10.1021/mp500284t

45. Брагина ОД, Чернов ВИ, Зельчан РВ, Синилкин ИГ, Медведева АА, Ларькина МС. Альтернативные каркасные белки в радионуклидной диагностике злокачественных новообразований. Бюллетень сибирской медицины. 2019;18(3):125–33. https://doi.org/10.20538/1682-0363-2019-3-125-133

46. Luo R, Liu H, Cheng Z. Protein scaffolds: antibody alternatives for cancer diagnosis and therapy. RSC Chem Biol. 2022;3(7):830–47. https://doi.org/10.1039/D2CB00094F

47. Gille H, Hulsmeyer M, Trentmann S, Matschiner G, Christian HJ, Meyer T, et al. Functional characterization of a VEGF-A-targeting Anticalin, prototype of a novel therapeutic human protein class. Angiogenesis. 2016;19(1): 79–94. https://doi.org/10.1007/s10456-015-9490-5

48. Williams GS, Mistry B, Guillard S, Ulrichsen JC, Sandercock AM, Wang J, et al. Phenotypic screening reveals TNFR2 as a promising target for cancer immunotherapy. Oncotarget. 2016;7(422):68278–91. https://doi.org/10.18632/oncotarget.11943

49. Sirois AR, Deny DA, Li Y, Fall YD, Moore SJ. Engineered Fn3 protein has targeted therapeutic effect on mesothelin-expressing cancer cells and increases tumor cell sensitivity to chemotherapy. Biotechnol Bioeng. 2020;117(2):330–41. https://doi.org/10.1002/bit.27204

50. Kohnehrouz BB, Talischian A, Dehnad A, Nayeri S. Novel recombinant traceable c-Met antagonist-avimer antibody mimetic obtained by bacterial expression analysis. Avicenna J Med Biotech. 2018;10(1):9–14. PMID:29296261

51. Gosmann D, Russelli L, Weber WA, Schwager M, Krackhardt AM, D’Alessandria C. Promise and challenges of clinical non-invasive T-cell tracking in the era of cancer immunotherapy. EJNMMI Res. 2022;12:5. https://doi.org/10.1186/s13550-022-00877-z

52. Shao F, Long Y, Ji H, Jiang D, Lei P, Lan X. Radionuclide-based molecular imaging allows CAR-T cellular visualization and therapeutic monitoring. Theranostics. 2021; 11(14):6800–17. https://doi.org/10.7150/thno.56989

53. Turner JH. Recent advances in theranostics and challenges for the future. Br J Radiol. 2018;91(1091): 20170893. https://doi.org/10.1259/bjr.20170893

54. Slebe M, Pouw JEE, Hashemi SMS, Menke-van der Houven van Oordt C, Yaqub MM, Bahce I. Current state and upcoming opportunities for immunoPET biomarkers in lung cancer. Lung Cancer. 2022;169:84–93. https://doi.org/10.1016/j.lungcan.2022.05.017

55. Lecocq Q, Zeven K, Vlaeminck YD, Martens S, Massa S, Goyvaerts C, et al. Noninvasive imagine of the immune checkpoint LAG-3 using nanobodies, from development tope-clinical use. Biomolecules. 2019;9(10):548. https://doi.org/10.3390/biom9100548

56. Eckerman K, Endo A. ICRP publication 107. Nuclear decay data for dosimetric calculations. Ann ICRP. 2008;38(3):7–96. https://doi.org/10.1016/j.icrp.2008.10.004

57. Papadimitroulas P, Loudos G, Nikiforidis GC, Kagadis GC. A dose point kernel database using GATE Monte Carlo simulation toolkit for nuclear medicine applications: comparison with other Monte Carlo codes. Med Phys. 2012;39(8):5238–47. https://doi.org/10.1118/1.4737096

58. Sgouros J, Bolch WE, Chiti A, Dewaraja YK, Emfietzoglou D, Hobbs RF, et al. ICRU report 96, dosimetry-guided radiopharmaceutical therapy. J Int Comm Rad Units Meas. 2021;21:1–212. https://doi.org/10.1177/14736691211060117

59. Blykers A, Schoonooghe S, Xavier C, D’hoe K, Laoui D, D’Huyvetter M, et al. PET imaging of macrophage mannose receptor-expressing macrophages in tumor stroma using 18 F-radiolabeled camelid single-domain antibody fragments. J Nucl Med. 2015;56(8):1265–71. https://doi.org/10.2967/jnumed.115.156828

60. Goodwin DA, Meares CF, Osen M. Biological properties of biotin-chelate conjugates for pretargeted diagnosis and therapy with the avidin/biotin system. J Nucl Med. 1998;39(10):1813–8. PMID:9776294

61. Boerman OC, van Schaijk FG, Oyen WJG, Corstens FHM. Pretargeted radioimmunotherapy of cancer: progress step by step. J Nucl Med. 2003;44(3):400–11. PMID:12621007

62. Verhoeven M, Seimbille Y, Dalm SU. Therapeutic applications of pretargeting. Pharmaceutcs. 2019;11(9): 434. https://doi.org/10.3390/pharmaceutics11090434

63. Knight JC, Cornelissen B. Bioorthogonal chemistry: implications for pretargeted nuclear (PET/SPECT) imaging and therapy. Am J Nucl Med Mol Imaging. 2014;4(2):96–113. https://doi.org/10.3390/biom9100548

64. Wong CH, Siah KW, Lo AW. Estimation of clinical trial success rates and related parameters. Biostatistics. 2018;20(2):273–86. https://doi.org/10.1093/biostatistics/kxx069

65. Lin A, Giuliano CJ, Palladino A, John KM, Abramowicz C, Yuan ML, et al. Off-target toxicity is a common mechanism of action of cancer drugs undergoing clinical trials. Sci Transl Med. 2019;11(509):eaaw8412. https://doi.org/10.1126/scitranslmed.aaw8412

66. Jagodinsky JC, Morris ZS. Priming and propagating anti-tumor immunity: Focal hypofractionated radiation for in situ vaccination and systemic targeted radionuclide theranostics for immunomodulation of tumor microenvironments. Semin Radiat Oncol. 2020;30(2):181–6. https://doi.org/10.1016/j.semradonc.2019.12.008