Vaccine-induced tumor regression requires a dynamic cooperation between T cells and myeloid cells at the tumor site
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Maxime Thoreau1,2,3,4, HweiXian Leong Penny5, KarWai Tan5, Fabienne Regnier1,2,3,4, Julia Miriam Weiss1,2,3,4, Bernett Lee5, Ludger Johannes6,7,8, Estelle Dransart6,7,8, Agnès Le Bon1,2,3, Jean-Pierre Abastado5, Eric Tartour9, Alain Trautmann1,2,3,4,*, Nadège Bercovici1,2,3,4,*
1Inserm, U1016, Institut Cochin, Paris, France
2Cnrs, UMR8104, Paris, France
3Université Paris Descartes, Sorbonne Paris Cité, Paris, France
4Equipe labellisée “Ligue contre le Cancer”, Paris, France
5Singapore Immunology Network, BMSI, A-STAR, Singapore
6Institut Curie, Paris, France
7INSERM U1143, Paris, France
8CNRS UMR3666, Paris, France
9Inserm U970, PARCC, Université Paris Descartes, Sorbonne Paris Cité, Paris, France
*These authors have contributed equally to this work
Nadège Bercovici, e-mail: firstname.lastname@example.org
Alain Trautmann, e-mail: email@example.com
Keywords: T lymphocytes, myeloid cells, vaccine, tumor regression, imaging
Abbreviations: TAM, tumor-associated macrophages; TIL, tumor-infiltrating T lymphocytes
Received: April 15, 2015 Accepted: July 29, 2015 Published: August 11, 2015
Most cancer immunotherapies under present investigation are based on the belief that cytotoxic T cells are the most important anti-tumoral immune cells, whereas intra-tumoral macrophages would rather play a pro-tumoral role. We have challenged this antagonistic point of view and searched for collaborative contributions by tumor-infiltrating T cells and macrophages, reminiscent of those observed in anti-infectious responses. We demonstrate that, in a model of therapeutic vaccination, cooperation between myeloid cells and T cells is indeed required for tumor rejection. Vaccination elicited an early rise of CD11b+ myeloid cells that preceded and conditioned the intra-tumoral accumulation of CD8+ T cells. Conversely, CD8+ T cells and IFNγ production activated myeloid cells were required for tumor regression. A 4-fold reduction of CD8+ T cell infiltrate in CXCR3KO mice did not prevent tumor regression, whereas a reduction of tumor-infiltrating myeloid cells significantly interfered with vaccine efficiency. We show that macrophages from regressing tumors can kill tumor cells in two ways: phagocytosis and TNFα release. Altogether, our data suggest new strategies to improve the efficiency of cancer immunotherapies, by promoting intra-tumoral cooperation between macrophages and T cells.
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