title: Tumor stroma and chemokines control T-cell migration into melanoma following Temozolomide treatment.
abstract: The infiltration of T lymphocytes within tumors is associated with better outcomes in cancer patients, yet current understanding of factors that influence T-lymphocyte infiltration into tumors remains incomplete. In our study, Temozolomide (TMZ), a chemotherapeutic drug used to treat metastatic melanoma, induced T-cell infiltration into transplanted melanoma and into genitourinary (GU) tumors in mice developing spontaneous melanoma. In contrast, TMZ treatment did not increase T-cell infiltration into cutaneous tumors, despite similar increases in the expression of the (C-X-C) chemokines CXCL9 and CXCL10 in all sites after TMZ exposure. Our findings reveal that the matrix architecture of the GU tumor stroma, and its ability to present CXCL9 and CXCL10 after TMZ treatment played a key role in favouring T-cell infiltration. We subsequently demonstrate that modifications of these key elements by combined collagenase and TMZ treatment induced T-cell infiltration into skin tumors. T cells accumulating within GU tumors after TMZ treatment exhibited T helper type-1 effector and cytolytic functional phenotypes, which are important for control of tumor growth. Our findings highlight the importance of the interaction between tumor stroma and chemokines in influencing T-cell migration into tumors, thereby impacting immune control of tumor growth. This knowledge will aid the development of strategies to promote T-cell infiltration into cancerous lesions and has the potential to markedly improve treatment outcomes.
authors.affiliation: Singapore Immunology Network; BMSI; A-STAR ; Singapore ; Department of Clinical Research; Singapore General Hospital ; Singapore.
authors.forename: Kar Wai
authors.initials: KW
authors.lastname: Tan
authors.affiliation: Singapore Immunology Network; BMSI; A-STAR ; Singapore.
authors.forename: Maximilien
authors.initials: M
authors.lastname: Evrard
authors.affiliation: Singapore Immunology Network; BMSI; A-STAR ; Singapore.
authors.forename: Muly
authors.initials: M
authors.lastname: Tham
authors.affiliation: Emerging Infectious Diseases (EID) Program; Duke-NUS Graduate Medical School ; Singapore.
authors.forename: Michelle
authors.initials: M
authors.lastname: Hong
authors.affiliation: Yong Loo Lin School of Medicine; National University of Singapore.
authors.forename: Caleb
authors.initials: C
authors.lastname: Huang
authors.affiliation: Department of Occupational and Environmental Health; Nagoya University Graduate School of Medicine ; Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.affiliation: Institut Cochin; INSERM Unit 1016; CNRS UMR 8104; Université Paris Descartes ; Paris, France.
authors.forename: Armelle
authors.initials: A
authors.lastname: Prevost-Blondel
authors.affiliation: Institut Cochin; INSERM Unit 1016; CNRS UMR 8104; Université Paris Descartes ; Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Donnadieu
authors.affiliation: Singapore Immunology Network; BMSI; A-STAR ; Singapore.
authors.forename: Lai Guan
authors.initials: LG
authors.lastname: Ng
authors.affiliation: Singapore Immunology Network; BMSI; A-STAR ; Singapore.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Abastado
keywords: CTL, cytolytic T lymphocyte; CXCL, Chemokine (C-X-C motif) ligand; ECM, extracellular matrix; GU, genitourinary; GZB, Granzyme B; HSPG, heparan sulphate proteoglycan; IFNγ, interferon γ; TAF, tumor-associated fibroblast; TILs, tumor-infiltrating lymphocytes; TMZ, Temozolomide; Th, T helper; Treg, T regulatory; WT, wild-type; chemokines; temozolomide; tumor stroma; tumor-infiltrating lymphocytes