New leads into the recruitment of anti-tumor T lymphocytes

A study by the tumor immunology team lead by Prof. Bruno Silva-Santos (photo, next to the first author of the study, Telma Lança), from Instituto de Medicina Molecular (Faculdade de Medicina da Universidade de Lisboa), has identified a molecular mechanism, based on the chemokine CCL2 and its receptor CCR2, responsible for the recruitment and tumor infiltration by anti-tumor gamma-delta T lmphocytes. This report, published in the The Journal of Immunology (from the American Association of Immunologists), was developed in an animal model (of melanoma) as well as with human peripheral blood lymphocytes, thus opening new perspectives for the manipulation of gamma-delta T lymphocytes in cancer immunotherapy.

Authors and affiliations:

Telma Lança⁽¹⁾, Maria Fernanda Costa⁽²⁾, Natacha Gonçalves-Sousa⁽¹⁾, Margarida Rei⁽¹⁾, Ana Rita Grosso⁽¹⁾, Carmen Penido⁽²⁾, and Bruno Silva-Santos^(1,3)

⁽¹⁾Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.

⁽²⁾Laboratório de Farmacologia Aplicada, Farmanguinhos, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.

^#Centro de Desenvolvimento Tecnológico em Saúde, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil.

⁽³⁾Instituto Gulbenkian de Ciência, Oeiras, Portugal.

Abstract:

Protective role of the inflammatory CCR2/CCL2 chemokine pathway through recruitment of type 1 cytotoxic gd T lymphocytes to tumor beds

Tumor-infiltrating lymphocytes (TILs) are important prognostic factors in cancer progression and key players in cancer immunotherapy. Although gd T-lymphocytes can target a diversity of tumor cell types, their clinical manipulation is hampered by our limited knowledge on the molecular cues that determine gd T cell migration toward tumors in vivo. Here we set out to identify the chemotactic signals that orchestrate tumor infiltration by gd T cells. We have used the pre-clinical transplantable B16 melanoma model to profile chemokines in tumor lesions and assess their impact on gd TIL recruitment in vivo. We show that the inflammatory chemokine CCL2 and its receptor CCR2 are necessary for the accumulation of gd TILs in B16 lesions, where they produce interferon-g and display potent cytotoxic functions. Moreover, CCL2 directed gd T cell migration in vitro toward tumor extracts, which was abrogated by anti-CCL2 neutralizing antibodies. Strikingly, the lack of gd TILs in TCRd-deficient but also in CCR2-deficient mice enhanced tumor growth in vivo, thus revealing an unanticipated protective role for CCR2/CCL2 through the recruitment of gd T cells. Importantly, we demonstrate that human Vd1 T cells, but not their Vd2 counterparts, express CCR2 and migrate to CCL2, whose expression is strongly deregulated in multiple human tumors of diverse origin, such as lung, prostate, liver or breast cancer. This work identifies a novel protective role for CCL2/CCR2 in the tumor microenvironment, while opening new perspectives for modulation of human Vd1 T cells in cancer immunotherapy.

Journal:

The Journal of Immunology

Link:

http://www.jimmunol.org/content/190/12/6673.long