Immunotherapy: targeting CTLA-4 / B7 axis and PD-1 / PD-L1 axis in anticancer therapy. Part 1. Immunologic aspects.



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Abstract

Cytotoxic T-lymphocyte antigen 4/B7 (CTLA-4/B7) and Programmed cell death protein 1/programmed cell death protein ligand 1 (PD-1/PD-L1) pathways are key regulators in T-cell activation and tolerance. PD-1 and CTLA-4 transmit a signal upon binding its ligand, which down regulate effector functions of CD4+ and CD8+ Т-cells. However, the role of these signaling cascades in immune responses is quite multifaceted. CTLA-4 is negative regulator of T-cell immune function, and CTLA-4 binds to B7 molecules (B7-1 (CD80) and B7-2 (CD86)) with higher affinity if compared with CD28 affinity. Furthermore, interaction of CTLA-4 and B7 molecules upregulates anti-inflammatory cytokines IL-10 and TGF-β production by T-regulatory cells (Tregs). Moreover, Treg cells are able to inhibit the T-cell stimulatory activity of activated antigen-presenting cells (APCs) by reducing their CD80/CD86 expression via CTLA-4-dependent trogocytosis. This CD80/CD86 reduction on APCs is able to suppress clonal expansion and survival of activated T-cell in lymphoid tissue. PD-1 is expressed at the cell surface of different cells, including effector activated CD4+ and CD8+ T cells. This molecule is critical for the survival and effector functions of activated antigen-specific T-cells in inflamed peripheral tissues. Furthermore, PD-1 stimulates anti-inflammatory cytokines production by Tregs upon binding its ligand (PD-L1 and PD-L2). CTLA-4/B7 axis and PD-1/PD-L1 axis are responsible for peripheral tolerance and cancer immune escape. This review is aimed to summarize the role of CTLA-4/B7 axis and PD-1/PD-L1 axis blockades in cancer immunotherapy.

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About the authors

Andrey Shukshin

Email: andrei.shukshinf@yandex.ru
ORCID iD: 0009-0009-0830-1733
Russian Federation

Artem Rubinstein

Author for correspondence.
Email: arrubin6@mail.ru
ORCID iD: 0000-0002-8493-5211
SPIN-code: 6025-1790

Alexey Golovkin

Email: golovkin_a@mail.ru
ORCID iD: 0000-0002-7577-628X
SPIN-code: 8803-2425

Olga Moiseeva

Email: moiseeva@almazovcentre.ru
ORCID iD: 0000-0002-7817-3847
SPIN-code: 1492-3900

Igor Kudryavtsev

Email: igorek1981@yandex.ru
ORCID iD: 0000-0001-7204-7850
SPIN-code: 4903-7636

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