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T Cells Kill Autologous Metastatic Renal Cell Carcinoma1
* Institut National de la Santé et de la Recherche Médicale Unité 487, Institut Fédératif de Recherche 54, Institut Gustave Roussy, Villejuif, France;
Département de Anatomopathology, Institut Mutualiste Montsouris, Paris, France;
Unité des Thérapies Innovantes, Institut Gustave Roussy, Villejuif, France; and
Innate Pharma, Marseille, France
Metastatic renal cell carcinoma, inherently resistant to conventional treatments, is considered immunogenic. Indeed, partial responses are obtained after treatment with cytokines such as IL-2 or IFN-
, suggesting that the immune system may control the tumor growth. In this study, we have investigated the ability of the main subset of peripheral 
lymphocytes, the V9V2-TCR T lymphocytes, to induce an effective cytotoxic response against autologous primary renal cell carcinoma lines. These T cells were expanded ex vivo using a V9V2 agonist, a synthetic phosphoantigen called Phosphostim. From 11 of 15 patients, the peripheral V9V2 T cells were amplified in vitro by stimulating PBMCs with IL-2 and Phosphostim molecule. These expanded V9V2 T cells express activation markers and exhibit an effector/memory phenotype. They display a selective lytic potential toward autologous primary renal tumor cells and not against renal NC. The lytic activity involves the perforin-granzyme pathway and is mainly TCR and NKG2D receptor dependent. Furthermore, an increased expression of MHC class I-related molecule A or B proteins, known ligands of NKG2D, are detected on primary renal tumor cells. Interestingly, from 2 of the 11 positive cultures in response to Phosphostim, expanded-V9V2 T cells present an expression of killer cell Ig-like receptors, suggesting their prior recruitment in vivo. Unexpectedly, on serial frozen sections from three tumors, we observe a lymphocyte infiltrate that was mainly composed of V9V2 T cells. These results outline that V9V2-TCR effectors may represent a promising approach for the treatment of metastatic renal cell carcinoma.
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