Researchers demonstrate dual benefit of killer T cells used in cancer immunotherapy

To grow, tumors depend on a specific structure called the tumor stroma. This includes blood vessels, which supply the nutrients needed 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 therefore has a poor prognosis. A team from the University of Geneva (UNIGE) has demonstrated how ‘killer’ T cells used in immunotherapy to eliminate cancer cells can also destroy tumor lymphatics, significantly reducing the risk of metastasis. Exploiting this synergistic effect could increase the effectiveness of treatments against cancers in which lymphangiogenesis is important, such as colorectal cancer, melanoma, or breast cancer. These results can be read in the magazine scientific 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 to cause secondary metastases elsewhere in the body. However, therapies to block tumor lymphangiogenesis have been disappointing so far. “Indeed, they also represent the pathway for some immune cells, the 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 in the Geneva Center for Inflammation Research from the UNIGE Faculty of Medicine, who led this work. “We must therefore find a balance to inhibit this mechanism without blocking it completely, and thus decipher its mechanism of action in detail”.

Identify a unique target

To do this, the scientists used so-called “killer” T lymphocytes used in immunotherapy protocols. “These T cells are immune cells that are specifically activated in the lab to eliminate tumor cells before they are injected into patients,” explains Laure Garnier, a junior lecturer in Stéphanie Hugues’ lab and first author of this work. Here we injected them into mice with melanoma. And when, 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, after becoming carriers of tumor identification markers, are also recognized as enemies by the T cells that attack them. This mechanism therefore disrupts the tumor-associated lymphatic system to significantly reduce the risk of metastasis without completely blocking it.

The research team confirmed these results with other approaches, such as vaccination, which aims to boost the immune system.

‘We also saw the destruction of lymphatic endothelial cells and with it a decrease in lymph node metastases, limiting the chance of secondary metastases. Moreover, since this action only takes place in the tumor microenvironment, no systemic effect is to be feared.”


Laure Garnier, first author

Increase synergies by choosing the right weapons

How can this effect be enhanced without compromising the functioning of the immune cells that the lymphatics need to enter the tumor? There are several options, such as intervention once immunity is established, or in combination with therapeutic protocols where the immune system is so strong that limiting lymphangiogenesis would not impair its function. Nevertheless, our results show that the most effective approach is to use killer T cells generated in the lab and thus ready to attack, to bypass the first activation phase, which can be problematic. says Stephanie Hugues .

Immunotherapies remain complex and are only used when traditional treatments have proved inconclusive. While promising, these therapies are not miracle cures and often cause serious side effects. That is why we want to understand the smallest biological processes at work,” conclude the authors.

Source:

Reference magazine:

Garnier, L., et al. (2022) IFN-γ-dependent tumor antigen cross-presentation by lymphatic endothelial cells promotes their killing by T cells and inhibits metastasis. Progress in science. doi.org/10.1126/sciaadv.abl5162

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