OncohematologyOncohematologyОнкогематология1818-83462413-4023Publishing House ABV Press52610.17650/1818-8346-2022-17-1-113-120THEORETICAL ASPECTS AND BASIC RESEARCH – INTO THE ONCOLOGICAL PRACTICEТЕОРЕТИЧЕСКИЕ АСПЕКТЫ И ФУНДАМЕНТАЛЬНЫЕ ИССЛЕДОВАНИЯ – В ПРАКТИКУ ВРАЧА-ОНКОЛОГАImmune system changes in the pathogenesis of neurofibromatosis type 1Изменения иммунной системы в патогенезе нейрофиброматоза 1-го типаhttps://orcid.org/0000-0002-4091-382XMustafinR. N.МустафинР. Н.
Russian Federation

Rustam N. Mustafin

3 Lenina St., Ufa 450008

Рустам Наилевич Мустафин

450008 Уфа, ул. Ленина, 3

ruji79@mail.ruBashkir State Medical University, Ministry of Health of RussiaФГБОУ ВО «Башкирский государственный медицинский университет» Минздрава России290120221711131202901202229012022https://oncohematology.abvpress.ru/ongm/article/view/526

Neurofibromatosis type 1 (NF1) is a hereditary tumor syndrome occurring with a frequency of 1: 3000 of the population. NF1 is caused by germline heterozygous mutations in the NF1 gene, which encodes the oncosuppressor neurofibromin. The disease has a specific progressive course with multiple neurofibromas, in the initiation and growth of which NF1+/ – mast cells, macrophages and lymphocytes play an important role. Accordingly, the deficiency of neurofibromin impairs the differentiation and correct functioning of immune system cells. This is evidenced by the increased risk of leukemia in patients with NF1 and the role of NF1 mutations in the development of sporadic hematological malignancies. The development of neurofibromas is associated with the fact that NF1–/ – Schwann cells stimulate the migration of mast cells into the tumor microenvironment, which actively degranulate. The released cytokines promote neoangiogenesis, inflammation, fibroblast proliferation and the production of excess collagen. Therefore, in the treatment of NF1, the use of ketotifen and a kit/ fms kinase inhibitor is recommended. Macrophages and T-lymphocytes in neurofibromas do not provide an antitumor response, but promote inflammation and tumor growth. They produce STAT3 (signal transducer and activator of transcription 3), TGF-β, EGFR, IL-6, IL-4, and PD-1. Therefore, a promising direction is NF1 therapy with STAT3 inhibitors and immune checkpoint inhibitors that block programmed cell death ligand 1 (PD-L1). Activation of MEK signaling pathways in NF1 leads to PD-L1 stimulation; therefore, MEK inhibitors, which also suppress the RAS/RAF/MEK/ERK system, turned out to be effective in the treatment of NF1. For the treatment of sporadic malignant neoplasms, in the development of which NF1 mutations play a role, the developed methods of NF1 therapy can be used.

Нейрофиброматоз 1-го типа (НФ1) – наследственный опухолевый синдром, встречающийся с частотой 1:3000 населения. НФ1 обусловлен герминативными гетерозиготными мутациями в гене NF1, который кодирует онкосупрессор нейрофибромин. Для заболевания характерно прогрессирующее течение с образованием множества нейрофибром, в инициировании и росте которых важную роль играют NF1+/– -тучные клетки, макрофаги и лимфоциты. Соответственно, дефицит нейрофибромина нарушает дифференцировку и корректное функционирование клеток иммунной системы. Об этом свидетельствуют повышенный риск развития лейкозов у больных НФ1 и роль мутаций NF1 в развитии спорадических гемобластозов. В нейрофибромах NF1–/– -клетки Шванна стимулируют миграцию мастоцитов, которые активно дегранулируют, способствуя неоангиогенезу, воспалению, пролиферации фибробластов и выработке ими избытка коллагена. В связи с этим в лечении НФ1 рекомендовано применение кетотифена и ингибитора kit/fms-киназы. Макрофаги и Т-лимфоциты в нейрофибромах не обеспечивают противоопухолевого ответа, а способствуют воспалению и росту опухоли. Они продуцируют сигнальный белок STAT3 (передатчик сигнала и активатор транскрипции 3), TGF-β (трансформирующий фактор роста β), EGFR (рецептор эпидермального фактора роста), IL-6, IL-4 (интерлейкины 6 и 4) и PD-1. Поэтому перспективным направлением является терапия НФ1 ингибиторами STAT3 и иммунными чекпойнт-ингибиторами, блокирующими лиганд программируемой клеточной гибели 1 (PD-L1). Активация сигнальных путей MEK при НФ1 приводит к стимуляции PD-L1, поэтому эффективными в лечении НФ1 оказались ингибиторы MEK, которые подавляют также систему RAS/RAF/MEK/ERK. Поскольку соматические мутации в гене NF1 играют роль в развитии спорадических злокачественных неоплазм, для их лечения могут быть использованы разрабатываемые методы терапии НФ1.

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