The dual benefit of killer T cells to prevent cancer metastasis

Killer-T cells (green) attack lymphatic vessels (red) in tumors and induce their death (cell death marker in white). Credit: UNIGE – Robert Pick / Stéphanie Hugues

Scientists from the University of Geneva highlight the unexpected effect of certain immunotherapies in preventing cancer metastases.

Tumors depend on a specific structure, the tumor stroma, to grow. This includes blood vessels, which provide the nutrients necessary for diseased cells to multiply, as well as lymphatic vessels, through which they migrate to metastasize. The formation of lymphatic vessels – a mechanism known as lymphangiogenesis – in and around a tumor is therefore of poor prognosis.

A team of scientists has demonstrated how ‘killer’ T cells used in immunotherapy to kill cancer cells can also destroy tumor lymphatic vessels, significantly reducing the risk of metastasis. Exploiting this synergistic effect could increase the efficacy of treatments against cancers where lymphangiogenesis is important, such as colorectal cancer, melanoma or breast cancer. These results of researchers from the University of Geneva (UNIGE) can be read in the journal Science Advances.

Killer T cells (also known as cytotoxic T cell or cytotoxic T lymphocyte) are a type of immune cell that can kill certain cells, such as foreign cells, cancer cells, and virus-infected cells. Killer T cells can be isolated from other blood cells, grown in the lab, and then given to a patient to kill cancer cells. A killer T cell is a type of white blood cell and a type of lymphocyte.

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 blocking it completely, 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 while, as expected, the killer lymphocytes destroyed the tumor cells, they also attacked the lymph endothelial cells that line the lymph 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 only takes place in the tumor microenvironment, no systemic effect is to be feared”, stresses Laure Garnier.

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”, specifies Stéphanie Hughes.

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,” conclude the authors.

Reference: “IFN-γ-dependent tumor antigen cross-presentation by lymphatic endothelial cells promotes their destruction by T cells and inhibits metastasis” by Laure Garnier, Robert Pick, Julien Montorfani, Mengzhu Sun, Dale Brighouse , Nicolas Liaudet, Thomas Kammertoens, Thomas Blankenstein, Nicolas Page, Jeremiah Bernier-Latamani, Ngoc Lan Tran, Tatiana V. Petrova, Doron Merkler, Christoph Scheiermann and Stéphanie Hugues, June 8, 2022, Scientists progress.
DOI: 10.1126/sciadv.abl5162

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