Identification of a novel population of highly cytotoxic c‐Met‐expressing CD8 ⁺ T lymphocytes

Abstract

CD8 cytotoxic T lymphocytes (CTLs) are critical mediators of anti-tumor immunity, and controlling the mechanisms that govern CTL functions could be crucial for enhancing patient outcome. Previously, we reported that hepatocyte growth factor (HGF) limits effective murine CTL responses via antigen-presenting cells. Here, we show that a fraction of murine effector CTLs expresses the HGF receptor c-Met (c-Met CTLs). Phenotypic and functional analysis of c-Met CTLs reveals that they display enhanced cytolytic capacities compared to their c-Met CTL counterparts. Furthermore, HGF directly restrains the cytolytic function of c-Met CTLs in cell-mediated cytotoxicity reactions and and abrogates T-cell responses against metastatic melanoma Finally, we establish in three murine tumor settings and in human melanoma tissues that c-Met CTLs are a naturally occurring CD8 T-cell population. Together, our findings suggest that the HGF/c-Met pathway could be exploited to control CD8 T-cell-mediated anti-tumor immunity.

The Emerging Role of the c-MET-HGF Axis in Non-small Cell Lung Cancer Tumor Immunology and Immunotherapy

“…c-MET inhibition may however, also act directly upon T-cells to enhance effector functions. The hypothesis is supported by experiments that indicate c-MET positive CD8 positive cells have increased ability to reduce melanoma pulmonary metastasis compared to c-MET negative CD8 positive cells, which can be abrogated by the addition of HGF (56) c-MET positive B-lymphocytes in solid tumors have not, to the authors knowledge been reported. However, the HGF/c-Met axis has been shown to play a role in survival of mature murine B lymphocytes via the CD74 pathway (57), and is a paracrine factor involved with regulating B cell adhesion in lymphoid tissue (58,59).…”

“…Hepatocyte growth factor can attenuate CD8 positive responses in mice due to effects on antigen presenting cells (APCs)/generating tolerogenic dendritic cells (54,55). c-Met expression has been identified in human melanoma samples (56) and a small percentage of murine cytotoxic T-cells express c-MET receptors in response to activation (56). c-MET positive CD8 positive T-cells are more cytotoxic than c-MET negative CD8 positive T-cells when assessed in vivo and in vitro (56).…”

“…c-Met expression has been identified in human melanoma samples (56) and a small percentage of murine cytotoxic T-cells express c-MET receptors in response to activation (56). c-MET positive CD8 positive T-cells are more cytotoxic than c-MET negative CD8 positive T-cells when assessed in vivo and in vitro (56). c-MET positive cytolytic T-cells expressed higher levels of granzyme B and perforin and showed a trend toward producing higher concentrations of IFN-γ and TNF-α.…”

“…However, when these cells were exposed to HGF in vivo, cytolytic effects and cytokine production were reduced. This suggests HGF acts to restrain immune responses (56). c-MET inhibition may however, also act directly upon T-cells to enhance effector functions.…”

GD2‐directed CAR‐T cells in combination with HGF‐targeted neutralizing antibody (AMG102) prevent primary tumor growth and metastasis in Ewing sarcoma

“…However, we do not exclude other possibilities that AMG102 could enhance the efficacy of CAR‐T cell therapy through other mechanisms. For example, previous reports demonstrated that HGF limits effective murine cytotoxic T lymphocyte (CTL) responses via antigen‐presenting cells or directly down‐modulates the cytolytic function of c‐Met+CTLs through regulation of cytotoxic effector molecule expression . Whether AMG102 treatment in EWS patients will abolish these limitations on CTLs warrants further investigation.…”