Novas pistas para o recrutamento de linfócitos T anti-tumorais

Um estudo do grupo de Oncoimunologia do Prof. Bruno Silva-Santos (foto ao lado, junto com a primeira autora, Telma Lança), do Instituto de Medicina Molecular (Faculdade de Medicina da Universidade de Lisboa), identificou um mecanismo molecular, baseado na quimiocina CCL2 e no seu receptor CCR2, responsável pelo recutamento e infiltração tumoral de linfócitos T gama-delta dotados de potente ação anti-tumoral. Este trabalho, publicado no The Journal of Immunology (da Associação Americana de Imunologistas), foi desenvolvido em modelo animal (de melanoma) e também com linfócitos periféricos do sangue humano, abrindo assim novas perspetivas para a manipulação dos linfócitos T gama-delta na imunoterapia do cancro.

Autores e afiliações:

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.

Revista:

The Journal of Immunology

Link:

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