title: CXCL4 mediates tumor regrowth after chemotherapy by suppression of antitumor immunity.
abstract: The recurrence of colorectal cancer after chemotherapy is the leading cause of its high mortality. We propose that elucidating the mechanisms of tumor regrowth after chemotherapy in tumor-bearing mice may provide new insights into tumor relapse in cancer patients. We firstly report the identification of a chemokine, CXCL4, that plays an important role in the molecular mechanism of cancer regrowth after chemotherapy. A syngenic transplantation tumor model was established with murine colon cancer CT26 cells and treated with 5-FU. Genome-wide gene expression analysis determined that CXCL4 was transiently upregulated in the tumor model. Systemic overexpression of CXCL4 accelerated cancer growth in vivo, but not in vitro. Conversely, the anti-CXCL4 monoclonal antibody (CXCL4-mab) retarded tumor-regrowth after 5-FU treatment in immune-competent mice, but not nude mice. The CXCL4-mab treatment increased the local expression levels of IFN-γ and Gran-b genes in the tumor-bed, and elevated the function of CTLs against CT26 cells. Thus, the colon cancer cells in responding to the cytotoxic stress of 5-FU produce a high level of CXCL4, which suppresses antitumor immunity to confer the residual cancer cells an advantage for regrowth after chemotherapy. Our findings provide a novel target for developing therapeutics aiming to increase antitumor immunity after chemotherapy.
authors.affiliation: a Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University ; Shanghai , PR China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: a Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University ; Shanghai , PR China.
authors.forename: Jing
authors.initials: J
authors.lastname: Gao
authors.affiliation: a Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University ; Shanghai , PR China.
authors.forename: Xia
authors.initials: X
authors.lastname: Wang
authors.affiliation: a Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University ; Shanghai , PR China.
authors.forename: Shaorong
authors.initials: S
authors.lastname: Deng
authors.affiliation: a Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University ; Shanghai , PR China.
authors.forename: Hao
authors.initials: H
authors.lastname: Ye
authors.affiliation: b Shanghai Municipality Key Laboratory of Veterinary Biotechnology; School of Agriculture and Biology; Shanghai Jiao Tong University ; Shanghai , PR China.
authors.forename: Wen
authors.initials: W
authors.lastname: Guan
authors.affiliation: a Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University ; Shanghai , PR China.
authors.forename: Mingyuan
authors.initials: M
authors.lastname: Wu
authors.affiliation: b Shanghai Municipality Key Laboratory of Veterinary Biotechnology; School of Agriculture and Biology; Shanghai Jiao Tong University ; Shanghai , PR China.
authors.forename: Shunying
authors.initials: S
authors.lastname: Zhu
authors.affiliation: b Shanghai Municipality Key Laboratory of Veterinary Biotechnology; School of Agriculture and Biology; Shanghai Jiao Tong University ; Shanghai , PR China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Yu
authors.affiliation: a Laboratory of Regeneromics; School of Pharmacy; Shanghai Jiao Tong University ; Shanghai , PR China.
authors.forename: Wei
authors.initials: W
authors.lastname: Han
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D005472:Fluorouracil / Q000494:pharmacology; D020869:Gene Expression Profiling; D006801:Humans; D056747:Immunomodulation / Q000187:drug effects; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D010978:Platelet Factor 4 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000964:Antimetabolites, Antineoplastic; D010978:Platelet Factor 4; D005472:Fluorouracil
keywords: CTLs; CXCL4; anti-tumor immunity; chemotherapy; colon cancer; regrowth; tumor microenvironment