title: High-dose cyclophosphamide induces specific tumor immunity with concomitant recruitment of LAMP1/CD107a-expressing CD4-positive T cells into tumor sites.
abstract: Cancer chemotherapy regimens, particularly those employing high-dose cytotoxic drugs such as cyclophosphamide (CTX), have been considered to be immune suppressive. However, we observed that a single administration of high-dose CTX abolished tumors arising from subcutaneous injection of a mouse hepatoma cell line and subsequently induced specific tumor immunity. Depletion of T cells, specifically CD4(+) T cells, abrogated the CTX-mediated tumor regression. CTX treatment induced the rapid recruitment of CD4(+) T cells into the tumors, and these recruited cells initiated expression of LAMP1/CD107a, a cytotoxic granule molecule, and granzyme B in the absence of antigen presentation at draining lymph nodes and proliferation in the tumor tissues. Moreover, CTX enhanced the expression of a CC chemokine, CCL3, in tumor tissues, and CTX-mediated tumor regression was attenuated in mice deficient in CCR5, the receptor for this chemokine. Consistently, less CTX-induced accumulation of intratumoral LAMP1/CD107a-expressing CD4(+) T cells was observed in mice receiving splenocytes derived from CCR5-deficient mice than in those receiving splenocytes derived from WT mice. Thus, CTX induces the expression of CCL3, which induces the intratumoral migration of CD4(+) T cells expressing cytotoxic molecules, leading to tumor eradication and subsequent specific tumor immunity.
authors.affiliation: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan; Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Fukui 910-1193, Japan.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Naito
authors.affiliation: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Baba
authors.affiliation: Division of Cell Biology, Biomedical Research Center, Graduate School of Medicine, Juntendo University, Bunkyo-ku, Tokyo 113-8421, Japan.
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Sasaki
authors.affiliation: Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, Eiheiji-cho, Fukui 910-1193, Japan.
authors.forename: Yasunari
authors.initials: Y
authors.lastname: Nakamoto
authors.affiliation: Division of Molecular Bioregulation, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan. Electronic address: mukaida@staff.kanazawa-u.ac.jp.
authors.forename: Naofumi
authors.initials: N
authors.lastname: Mukaida
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D054405:Chemokine CCL3 / Q000032:analysis; D003520:Cyclophosphamide / Q000494:pharmacology*; D052118:Lysosomal-Associated Membrane Protein 1 / Q000032:analysis*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009374:Neoplasms, Experimental / Q000276:immunology*; D019713:Receptors, CCR5 / Q000032:analysis
chemical_list: C515429:CCL3 protein, human; C000592874:CCR5 protein, mouse; D054405:Chemokine CCL3; D052118:Lysosomal-Associated Membrane Protein 1; D019713:Receptors, CCR5; D003520:Cyclophosphamide
keywords: CC chemokine; CD4(+) T cell; Cytolytic T cell; LAMP1/CD107a