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Tumor Rejection and Immune Memory Elicited by Locally Released LEC Chemokine Are Associated with an Impressive Recruitment of APCs, Lymphocytes, and Granulocytes¹

Mirella Giovarelli^2,*, Paola Cappello^*, Guido Forni^*, Theodora Salcedo, Paul A. Moore, David W. LeFleur, Bernadetta Nardelli, Emma Di Carlo, Pier-Luigi Lollini^§, Steve Ruben, Stephen Ullrich, Gianni Garotta^3, and Piero Musiani

^* Department of Clinical and Biological Sciences, University of Torino, Orbassano, Italy; Departments of Cell Biology and Molecular Biology, Human Genome Sciences, Inc., Rockville, MD 20850; Department of Oncology and Neurosciences, University of Chieti, Chieti, Italy; and ^§ Institute for Cancer Research, University of Bologna, Bologna, Italy

The human ß chemokine known as LEC (also called NCC-4, HCC-4, or LMC) displays chemotactic activity for monocytes and dendritic cells. The possibility that its local presence increases tumor immunogenicity is addressed in this paper. TSA parental cells (TSA-pc) are poorly immunogenic adenocarcinoma cells that grow progressively, kill both nu/nu and syngeneic BALB/c mice, and give rise to lung metastases. TSA cells engineered to release LEC (TSA-LEC) are still able to grow in nu/nu mice, but are promptly rejected and display a marginal metastatic phenotype in BALB/c mice. Rejection is associated with a marked T lymphocyte and granulocyte infiltration, along with extensive macrophage and dendritic cell recruitment. NK cells and CD4⁺ T lymphocytes are uninfluential in TSA-LEC cell rejection, whereas both CD8⁺ lymphocytes and polymorphonuclear leukocytes play a major role. An antitumor immune memory is established very quickly after rejection, since 6 days later 75% of BALB/c mice were already resistant to a TSA-pc challenge. Spleen cells from rejecting mice display specific cytotoxic activity against TSA-pc and secrete IFN- and IL-2 when restimulated by TSA-pc. The ability of LEC to markedly improve recognition of poorly immunogenic cells by promoting APC-T cell cross-talk suggests that it could be an effective component of antitumor vaccines.

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