To grow, tumors rely on a specific structure, the tumor stroma. This includes blood vessels, which provide the nutrients necessary for diseased cells to multiply, and lymphatic vessels, through which they migrate to metastasize. The development of lymphatic vessels – a mechanism known as lymphangiogenesis – in and around a tumor is therefore of poor prognosis. A team from the University of Geneva (UNIGE) has demonstrated how “killer” T lymphocytes used in immunotherapy to eliminate cancer cells can also destroy tumor lymphatic vessels, thus greatly reducing the risk of metastases. Harnessing this synergistic effect could increase the efficacy of treatments for cancers where lymphangiogenesis is important, such as colorectal cancer, melanoma, or breast cancer. These results can be read in the journal Scientists progress.
The lymphatic system is the main route by which cancer cells spread in the body. They first colonize the sentinel lymph nodes and then move on to give rise to secondary metastases elsewhere in the body. However, therapies to block tumor lymphangiogenesis have so far been disappointing. “Indeed, they also represent the pathway for certain immune cells, dendritic cells, to exit the tumor and activate anti-tumor killer T cells,” explains Stéphanie Hugues, associate professor in the Department of Pathology and Immunology. and at the University of Geneva. Inflammation Research Center of the UNIGE Faculty of Medicine, which led this work. “We must therefore find a balance in order to inhibit this mechanism without completely blocking it, and thus decipher in detail its mode of action”.
Identify a single target
To do this, the scientists used so-called “killer” T lymphocytes used in immunotherapy protocols. “These T lymphocytes are immune cells specifically activated in the laboratory to eliminate tumor cells, before being injected into patients”, explains Laure Garnier, lecturer in the laboratory of Stéphanie Hugues and first author of this work. “Here we injected them into mice with melanoma. And if, as expected, the killer lymphocytes destroyed the tumor cells, they also attacked the lymphatic endothelial cells that line the lymphatic vessels.”
Indeed, the destruction of cancer cells leads to the release of tumor antigens. These small cancerous parts are then captured by the lymphatic endothelial cells which, having become carriers of tumor identification markers, are also recognized as enemies by the T lymphocytes which attack them. This mechanism therefore disrupts the tumor-associated lymphatic system to significantly reduce the risk of metastasis without blocking it entirely.
The research team confirmed these results with other approaches, such as vaccination, which aims to strengthen the immune system.
“We also observed the destruction of lymphatic endothelial cells, and consequently a reduction in lymph node metastases, thus limiting the risk of secondary metastases. Moreover, since this action takes place only in the tumor microenvironment, no systemic effects are to be feared.”
Laure Garnier, first author
Increase synergies by choosing the right weapons
How can this effect be reinforced without compromising the action of immune cells, which need the lymphatic vessels to penetrate the tumour? There are several options, such as intervening once immunity is established, or in conjunction with therapeutic protocols where the immune system is so strong that limiting lymphangiogenesis would not alter its functioning. “Nevertheless, our results show that the most effective approach is to use killer T cells generated in the laboratory, and therefore ready to attack, in order to circumvent the first phase of activation, which can prove to be problematic” , says Stéphanie Hugues. .
Immunotherapies remain complex and are only used when traditional treatments have proven inconclusive. ”Although they are very promising, these therapies are not miracle solutions and often cause severe side effects. This is why we want to understand the smallest biological processes at work,” the authors conclude.
Garnier, L. et al. (2022) Cross-presentation of IFN-γ-dependent tumor antigen by lymphatic endothelial cells promotes their destruction by T cells and inhibits metastasis. Scientific advances. doi.org/10.1126/sciadv.abl5162.
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