Effect of Bruton Tyrosine Kinase Inhibitors on T-Lymphocytes and Tumor Microenvironment Cells in B-Cell Lymphoproliferative Diseases

Bruton tyrosine kinase (BTK) inhibitors have drastically changed the approaches to the treatment of B-cell chronic lymphoproliferative diseases (LPD) as they considerably improve survival rates and quality of life of patients. Despite of their high efficacy, about half of the patients develop resistance to covalent BTK inhibitors due to point mutations in the BTK gene on the substrate binding site. This paper systematically reviews the present-day knowledge of mechanisms underlying the resistance to BTK inhibitors and methods to overcome it as well as the effect of these drugs on T-lymphocytes and tumor microenvironment cells in LPDs. It is demonstrated that non-covalent BTK inhibitors can sustain their activity against mutated BTK forms, whereas some degraders enable selective BTK protein breakdown irrespective of mutation status. Moreover, BTK inhibitors produce a considerable effect on tumor microenvironment, i.e., they reduce the number and activity of myeloid suppressor cells, foster changing polarization of macrophages from pro- (M2) to antitumor (M1) phenotype, and increase functional activity of T-lymphocytes by shifting the balance from Th2 to Th1. Consequently, immunomodulatory properties of BTK inhibitors contribute to antitumor immune response and can be successfully exploited in the combined treatment, also as a part of infection and inflammation therapy.

• Yuliya Sergeevna Efremova Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya ul., Saint Petersburg, Russian Federation, 191024 ; Saint Petersburg State Pediatric Medical University, 2 Litovskaya ul., Saint Petersburg, Russian Federation, 194100 https://orcid.org/0000-0002-2387-2712 (unauthenticated)
• T.V. Glazanova Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya ul., Saint Petersburg, Russian Federation, 191024 https://orcid.org/0000-0002-1022-8127 (unauthenticated)
• N.A. Romanenko Russian Research Institute of Hematology and Transfusiology, 16 2-ya Sovetskaya ul., Saint Petersburg, Russian Federation, 191024 ; II Mechnikov North-Western State Medical University, 47 Piskarevskii pr-t, Saint Petersburg, Russian Federation, 195067 https://orcid.org/0000-0002-7602-9382 (unauthenticated)

1. Barf T, Covey T, Izumi R, et al. Acalabrutinib (ACP-196): A Covalent Bruton Tyrosine Kinase Inhibitor with a Differentiated Selectivity and In Vivo Potency Profile. J Pharmacol Exp Ther. 2017;363(2):240–52. doi: 10.1124/jpet.117.242909. DOI: https://doi.org/10.1124/jpet.117.242909
2. Торшина Ю.С., Серебряная Н.Б., Глазанова Т.В. и др. Иммуномодулирующие эффекты противоопухолевых препаратов — ингибиторов тирозинкиназы Брутона — и возможности их использования при аллергических и инфекционных заболеваниях. Медицинская иммунология. 2023;25(5):1253–8. doi: 10.15789/1563-0625-ieo-2816. [Torshina Yu.S., Serebryanaya N.B., Glazanova T.V., et al. Immunomodulating effects of antitumor drugs Bruton tyrosine kinase inhibitors and the possibility of their use in allergic and infectious diseases. Medical Immunology (Russia). 2023;25(5):1253–8. doi: 10.15789/1563-0625-ieo-2816. (In Russ)] DOI: https://doi.org/10.15789/1563-0625-IEO-2816
3. Moreno C, Muñoz C, Terol MJ, et al. Restoration of the immune function as a complementary strategy to treat chronic lymphocytic leukemia effectively. J Exp Clin Cancer Res. 2021;40(1):321. doi: 10.1186/s13046-021-02115-1. DOI: https://doi.org/10.1186/s13046-021-02115-1
4. Awan FT, Schuh A, Brown JR, et al. Acalabrutinib monotherapy in patients with chronic lymphocytic leukemia who are intolerant to ibrutinib. Blood Adv. 2019;3(9):1553–62. doi: 10.1182/bloodadvances.2018030007. DOI: https://doi.org/10.1182/bloodadvances.2018030007
5. Zi F, Yu L, Shi Q, et al. Ibrutinib in CLL/SLL: From bench to bedside (Review). Oncol Rep. 2019;42(6):2213–27. doi: 10.3892/or.2019.7364. DOI: https://doi.org/10.3892/or.2019.7364
6. Estupiñán, HY, Wang Q, Berglöf A, et al. BTK gatekeeper residue variation combined with cysteine 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib, ibrutinib and zanubrutinib. Leukemia. 2021;35(5):1317–29. doi: 10.1038/s41375-021-01123-6. DOI: https://doi.org/10.1038/s41375-021-01123-6
7. Zain R, Vihinen M. Structure-Function Relationships of Covalent and Non-Covalent BTK Inhibitors. Front Immunol. 2021;12:694853. doi: 10.3389/fimmu.2021.694853. DOI: https://doi.org/10.3389/fimmu.2021.694853
8. Herman SEM, Gordon AL, Hertlein E, et al. Bruton tyrosine kinase represents a promising therapeutic target for treatment of chronic lymphocytic leukemia and is effectively targeted by PCI-32765. Blood. 2011;117(23):6287–96. doi: 10.1182/blood-2011-01-328484. DOI: https://doi.org/10.1182/blood-2011-01-328484
9. McMullen JR, Boey EJH, Ooi JYY, et al. Ibrutinib increases the risk of atrial fibrillation, potentially through inhibition of cardiac PI3K-Akt signaling. Blood. 2014;124(25):3829–30. doi: 10.1182/blood-2014-10-604272. DOI: https://doi.org/10.1182/blood-2014-10-604272
10. Pal Singh S, Dammeijer F, Hendriks RW. Role of Brutons tyrosine kinase in B cells and malignancies. Mol Cancer. 2018;17(1):57. doi: 10.1186/s12943-018-0779-z. DOI: https://doi.org/10.1186/s12943-018-0779-z
11. Brown JR, Eichhorst B, Hillmen P, et al. Zanubrutinib or ibrutinib in relapsed or refractory chronic lymphocytic leukemia. N Engl J Med. 2023;388(4):319–32. doi: 10.1056/NEJMoa2211582. DOI: https://doi.org/10.1056/NEJMoa2211582
12. Byrd JC, Harrington B, O’Brien S, et al. Acalabrutinib (ACP-196) in relapsed chronic lymphocytic leukemia. N Engl J Med. 2016;374(4):323–32. doi: 10.1056/NEJMoa1509981. DOI: https://doi.org/10.1056/NEJMoa1509981
13. Tam CS, Opat S, D’Sa S, et al. A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study. Blood. 2020;136(18):2038–50. doi: 10.1182/blood.2020006844. DOI: https://doi.org/10.1182/blood.2020006844
14. Quinquenel A, Fornecker L-M, Letestu R, et al. Prevalence of BTK and PLCG2 mutations in a real-life CLL cohort still on ibrutinib after 3 years: a FILO group study. Blood. 2019;134(7):641–4. doi: 10.1182/blood.2019000854. DOI: https://doi.org/10.1182/blood.2019000854
15. Nawaratne V, Sondhi AK, Abdel-Wahab O, Taylor J. New Means and Challenges in the Targeting of BTK. Clin Cancer Res. 2024;30(11):2333–41. doi: 10.1158/1078-0432.CCR-23-0409. DOI: https://doi.org/10.1158/1078-0432.CCR-23-0409
16. Gomez EB, Ebata K, Randeria HS, et al. Pirtobrutinib preclinical characterization: a highly selective, non-covalent (reversible) BTK inhibitor. Blood. 2023;142(1):62–72. doi: 10.1182/blood.2022018674. DOI: https://doi.org/10.1182/blood.2022018674
17. Mato AR, Shah NN, Jurczak W, et al. Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study. Lancet. 2021;397(10277):892–901. doi: 10.1016/S0140-6736(21)00224-5. DOI: https://doi.org/10.1016/S0140-6736(21)00224-5
18. Tam C, Thompson PA. BTK inhibitors in CLL: second-generation drugs and beyond. Blood Adv. 2024;8(9):2300–9. doi: 10.1182/bloodadvances.2023012221. DOI: https://doi.org/10.1182/bloodadvances.2023012221
19. Montoya S, Bourcier J, Thompson MC, et al. Kinase dead BTK mutations confer resistance to covalent and noncovalent BTK inhibitors but are susceptible to clinical stage BTK degraders. Blood. 2022;140(Suppl 1):1811–3. doi: 10.1182/blood-2022-163268. DOI: https://doi.org/10.1182/blood-2022-163268
20. Mato AR, Wierda WG, Ai WZ, et al. NX-2127-001, a first-in-human trial of NX-2127, a Bruton’s tyrosine kinase-targeted protein degrader, in patients with relapsed or refractory chronic lymphocytic leukemia and B-cell malignancies. Blood. 2022;140(Suppl 1):2329–32. doi: 10.1182/blood-2022-164772. DOI: https://doi.org/10.1182/blood-2022-164772
21. Nadeem A, Ahmad SF, Al-Harbi NO, et al. Bruton’s tyrosine kinase inhibition attenuates oxidative stress in systemic immune cells and renal compartment during sepsis-induced acute kidney injury in mice. Int Immunopharmacol. 2021;90:107123. doi: 10.1016/j.intimp.2020.107123. DOI: https://doi.org/10.1016/j.intimp.2020.107123
22. Niemann CU, Herman SE, Maric I, et al. Disruption of in vivo Chronic Lymphocytic Leukemia Tumor‐Microenvironment Interactions by Ibrutinib‐Findings from an Investigator‐Initiated Phase II Study. Clin Cancer Res. 2016;22(7):1572–82. doi: 10.1158/1078-0432.CCR-15-1965. DOI: https://doi.org/10.1158/1078-0432.CCR-15-1965
23. Ni Gabhann J, Hams E, Smith S, et al. Btk regulates macrophage polarization in response to lipopolysaccharide. PLoS One. 2014;9(1):e85834. doi: 10.1371/journal.pone.0085834. DOI: https://doi.org/10.1371/journal.pone.0085834
24. Noy R, Pollard JW. Tumor-associated macrophages: from mechanisms to therapy. Immunity. 2014;41(1):49–61. doi: 10.1016/j.immuni.2014.06.010. DOI: https://doi.org/10.1016/j.immuni.2014.06.010
25. Page TH, Urbaniak AM, Espirito Santo AI, et al. Bruton’s tyrosine kinase regulates TLR7/8-induced TNF transcription via nuclear factor-κB recruitment. Biochem Biophys Res Commun. 2018;499(2):260–6. doi: 10.1016/j.bbrc.2018.03.140. DOI: https://doi.org/10.1016/j.bbrc.2018.03.140
26. Ormsby T, Schlecker E, Ferdin J, et al. Btk is a positive regulator in the TREM-1/DAP12 signaling pathway. Blood. 2011;118(4):936–45. doi: 10.1182/blood-2010-11-317016. DOI: https://doi.org/10.1182/blood-2010-11-317016
27. Fiorcari S, Maffei R, Vallerini D, et al. BTK Inhibition Impairs the Innate Response Against Fungal Infection in Patients With Chronic Lymphocytic Leukemia. Front Immunol. 2020;11:2158. doi: 10.3389/fimmu.2020.02158. DOI: https://doi.org/10.3389/fimmu.2020.02158
28. Estupiñán HY, Berglöf A, Zain R, Smith CIE. Comparative Analysis of BTK Inhibitors and Mechanisms Underlying Adverse Effects. Front Cell Dev Biol. 2021;9:630942. doi: 10.3389/fcell.2021.630942. DOI: https://doi.org/10.3389/fcell.2021.630942
29. Dubovsky JA, Beckwith KA, Natarajan G, et al. Ibrutinib is an irreversible molecular inhibitor of ITK driving a Th1-selective pressure in T lymphocytes. Blood. 2013;122(15):2539–49. doi: 10.1182/blood-2013-06-507947. DOI: https://doi.org/10.1182/blood-2013-06-507947
30. Montauti E, Oh DY, Fong L. CD4+ T cells in antitumor immunity. Trends Cancer. 2024;10(10):969–85. doi: 10.1016/j.trecan.2024.07.009. DOI: https://doi.org/10.1016/j.trecan.2024.07.009
31. Cachot A, Bilous M, Liu YC, et al. Tumor-specific cytolytic CD4 T cells mediate immunity against human cancer. Sci Adv. 2021;7(9):eabe3348. doi: 10.1126/sciadv.abe3348. DOI: https://doi.org/10.1126/sciadv.abe3348
32. Wiedemann A, Depoil D, Faroudi M, Valitutti S. Cytotoxic T-lymphocytes kill multiple targets simultaneously via spatiotemporal uncoupling of lytic and stimulatory synapses. Proc Natl Acad Sci USA. 2006;103(29):10985–90. doi: 10.1073/pnas.0600651103. DOI: https://doi.org/10.1073/pnas.0600651103
33. Liu Y, Song Y, Yin Q. Effects of ibrutinib on T-cell immunity in patients with chronic lymphocytic leukemia. Front Immunol. 2022;13:962552. doi: 10.3389/fimmu.2022.962552. DOI: https://doi.org/10.3389/fimmu.2022.962552
34. Рuzzolo MC, Del Giudice I, Peragine N, et al. Th2/Th1 shift under ibrutinib treatment in chronic lymphocytic leukemia. Front Oncol. 2021;11:637186. doi: 10.3389/fonc.2021.637186. DOI: https://doi.org/10.3389/fonc.2021.637186