c-Met+ Cytotoxic T Lymphocytes Exhibit Enhanced Cytotoxicity in Mice and Humans In Vitro Tumor Models

Summary

CD8+ cytotoxic T lymphocytes (CTLs) play a crucial role in anti-tumor immunity. In a previous study, the authors of this article, lead by GCIR member Patrice Lalive, identified a subset of murine effector CTLs expressing the hepatocyte growth factor (HGF) receptor, c-Met (c-Met+ CTLs), that are endowed with enhanced cytolytic capacity. HGF directly inhibited the cytolytic function of c-Met+ CTLs, both in 2D in vitro assays and in vivo, leading to reduced T cell responses against metastatic melanoma. To further investigate the role of c-Met+ CTLs in a three-dimensional (3D) setting, they studied their function within B16 melanoma spheroids and examined the impact of cell–cell contact on the modulation of inhibitory checkpoint molecules’ expression, such as KLRG1, PD-1, and CTLA-4. Additionally, the authors evaluated the cytolytic capacity of human CTL clones expressing c-Met (c-Met+) and compared it to c-Met− CTL clones. Their results indicated that, similar to their murine counterparts, c-Met+ human CTL clones exhibited increased cytolytic activity compared to c-Met− CTL clones, and this enhanced function was negatively regulated by the presence of HGF. Taken together, these findings highlight the potential of targeting the HGF/c-Met pathway to modulate CTL-mediated anti-tumor immunity. This research holds promise for developing strategies to enhance the effectiveness of CTL-based immunotherapies against cancer.

Funding: This work is supported by the Swiss National Science Foundation and the Private Foundation of the HUG.

Full article: https://doi.org/10.3390/biomedicines11123123

Why is it important?

Malignant tumours are found in a microenvironment composed of various cell types, such as stromal cells, neutrophils, dendritic cells and macrophages. Some of these cells release hepatocyte growth factor (HGF) and promote the activation of its receptor, called c-Met, within tumour cells. The expression of c-Met by tumour cells has been linked to poor prognosis in different types of cancer, such as gastro-oesophageal adenocarcinoma, cholangiocarcinoma, colon cancer, kidney cancer, glioblastoma, melanoma and lung cancer.

In addition, the authors of this work have successfully demonstrated the presence of c-Met expressing cytotoxic T lymphocytes (CTL) in an in vitro mouse model of melanoma. When c-Met is expressed in CTLs, the tumour outcome is the opposite, producing a specific lysis of tumour cells. Based on these results, and in order to shed light on these processes, the authors proceeded to explore the presence of c-Met CTL cells in human cancers. They showed, for the first time, that human CD8+ T-cell clones derived from cancer patients expressed the c-Met receptor. More importantly, the CD8+ c-Met+ clones produced higher levels of anti-tumour effector molecules compared to their CD8+ c-Met- counterparts and showed significant tumour cell-specific lysis capacity, which decreased after in vitro treatment with HGF.

This observation is particularly important because numerous small molecule inhibitors and monoclonal antibodies that recognise c-Met, such as capminatinib, a highly potent and selective c-Met inhibitor recently approved for lung cancer, have been tested in preclinical studies. However, in light of this study, it is crucial to consider the potential impact of these therapies on c-Met-expressing cytotoxic T cells within the tumour microenvironment.

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