Autologous therapeutic vaccine APAVAC®
Lymph node system role |
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There are several classes of lymphocytes |
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In addition to B lymphocytes, which are responsible for producing antibodies to activate humoral immunity, there are 3 classes of T lymphocytes responsible for cellular immunity..
The antigen receptors of these T lymphocytes only recognise peptide fragments of protein antigens which are linked to specialised MHC peptide presentation molecules on the surface of specialised cells called Antigen Presenting Cells (APCs)..
- T helper lymphocytes (CD4+ T lymphocytes) because they help B lymphocytes in particular to produce antibodies
- CTL cytotoxic T lymphocytes (CD8+ T lymphocytes) because they kill tumour cells
- Regulatory T lymphocytes (a special subset of CD4+ T lymphocytes), whose function is to prevent or attenuate immune responses.
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The following table provides a summary of the main characteristics of lymphocytes in the adaptive immune system. |
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Immune mechanisms for tumour rejection
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The main immune mechanism to eradicate tumours is based on an innate pathway using natural killer (NK) cells and an adaptive pathway using tumour antigen-specific T lymphocytes (CTL). Because tumour cells are genetically unstable, they synthesise modified proteins that form antigens normally recognised by the immune system (TAA: tumour-associated antigens).
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NKs recognise cancer cells without the intervention of immune recognition and presentation of TAA. The vast majority of tumour neoantigens that trigger adaptive immune responses in tumour-bearing individuals are cytosolic or nuclear cellular proteins synthesised endogenously, primed by proteasomes and presented as peptides associated with class I Major Histocompatibility Complex (MHC) molecules.
These antigens are recognised by CD8+ CTLs and restricted by MHC class I molecules whose function is to destroy the cells producing these antigens. CTL responses against tumours are initiated by the recognition of tumour antigens on antigen-presenting cells (APCs). APCs are able to ingest tumour cells or their antigens and prepare and present them to naive immune CD8+ CTL cells, particularly in lymph nodes.
This presentation of peptides derived from ingested tumour antigens occurs on MHC class II molecules and enables them to be recognised by CD4+ CTLs. This is termed cross-priming.
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Role of heat shock proteins in CTLs cross-priming
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This presentation of peptides derived from ingested tumour antigens occurs on MHC class II molecules and enables them to be recognised by CD4+ CTLs. This is termed cross-priming.
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Heat Shock Proteins are molecular chaperones that bind and stabilise proteins at intermediate stages of folding, assembly, translocation across membranes and degradation.
Cancer cells under metabolic stress synthesise large quantities of stress proteins, which are also found in the blood (1), according to Ciocca et al. In addition to their role in stabilising proteins under conditions of cellular stress, HSPs play a role in triggering the immune response. HSPs transport peptide antigens, which are chaperoned by these proteins, for presentation to the cells of the immune system:
- The peptides generated by the proteasome in the cytoplasm are transported across the endoplasmic reticulum membrane by TAP transporters, loaded into MHC class I proteins and presented to cytotoxic CD8+ cells.
- The peptides generated by the acid hydrolases in the lysosome are loaded onto MHC class II proteins and presented to CD4+ cells (2).
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What role do lymph nodes play in the immune response?
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In the lymph node, the antibodies recruit new lymphocytes to fight the tumour. As a result, the way the treatment works in the lymph node is very different from the way it works in the tumour. In the tumour, CD8+ killer T lymphocytes bind and kill tumour cells, but in the lymph node they also interact with CD4+ helper T lymphocytes. These follicular helper cells do not attack the tumour directly, but secrete interleukin 4 in particular, which stimulates the proliferation of killer cells. Recent work by a Pasteur Institute team(3) has highlighted the key role of the lymph node in immunotherapy, which must be considered when monitoring patients' treatment. The aim is to give the recruited cells time to leave the lymph node and reach the tumour, thereby boosting the immune response already in place.
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What about the ‘sentinel lymph node’ procedure?
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In human medicine, in many types of cancer, the identification and removal of affected lymph nodes is essential for accurate cancer management, including treatment and prognosis. Historically, lymphadenectomy and subsequent radical resection based on regional anatomy, palpation and lymph node aspiration were considered sufficient. However, modern approaches with sentinel lymph node (SLN) mapping have increased the accuracy of surgical decision-making. In veterinary patients, preoperative and intraoperative sentinel lymph node mapping techniques are similar to those used in human medicine. Although many of these techniques are highly effective, the main challenges posed by current methodologies are their sensitivity and specificity for the presence of cancer. For all these reasons, several authors in veterinary medicine feel that it is impossible to consider sentinel lymph node detection and removal as a ‘gold standard’ (4). In fact, given the current state of knowledge, the benefit/risk balance does not appear to be in favour of systematically recommending removal of the sentinel lymph node, which should be reserved for cases of negative exhaustive extension tests.
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APAVAC® treatment enables tumour antigens to be fixed, concentrated and vectorised, with the aim of activating the animal's specific immune system against its own tumour when combined with heat shock proteins. Its mechanism of action is based on the direct cytotoxic effect of CD8+ T lymphocytes, but also involves the activation of helper CD4+ T lymphocytes, which are essential for the continuous and prolonged stimulation of cytotoxic effector cells against tumour cells. The lymph node system is of vital importance in maintaining the efficacy of immunotherapy throughout the full 5-month vaccination schedule. Under no circumstances should sentinel lymph node excision be systematic.
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REFERENCES
1. Ciocca DR,
Calderwood SK. Heat shock proteins in cancer: diagnostic, prognostic,
predictive, and treatment implications. Cell Stress Chaperones. Summer
2005;10(2):86‑103.
2. Schuette V,
Burgdorf S. The ins-and-outs of endosomal antigens for cross-presentation. Curr Opin Immunol. févr 2014;26:63‑8.
3. Ruggiu M, Guérin MV, Corre B, Bardou M, Alonso
R, Russo E, et al. Anti-PD-1 therapy triggers Tfh cell-dependent IL-4
release to boost CD8 T cell responses in tumor-draining lymph nodes. J Exp Med. 1 avr 2024;221(4).
4. Keravel O. Médecins et chirurgiens
unis contre le cancer. Médecine Chirurgie Anim. juin 2023;(8):78‑82.
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Would you like to discuss the use of Apavac on an animal in your care ? Would you like to order ? contact us by e-mail : adv@hastim.fr or by phone : +33 5 34 47 86 10 |
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