title: CXCR1 as a novel target for directing reactive T cells toward melanoma: implications for adoptive cell transfer immunotherapy.
abstract: Adoptive cell transfer therapy with reactive T cells is one of the most promising immunotherapeutic modalities for metastatic melanoma patients. Homing of the transferred T cells to all tumor sites in sufficient numbers is of great importance. Here, we seek to exploit endogenous chemotactic signals in order to manipulate and enhance the directional trafficking of transferred T cells toward melanoma. Chemokine profiling of 15 melanoma cultures shows that CXCL1 and CXCL8 are abundantly expressed and secreted from melanoma cultures. However, the complimentary analysis on 40 melanoma patient-derived tumor-infiltrating lymphocytes (TIL) proves that the corresponding chemokine receptors are either not expressed (CXCR2) or expressed at low levels (CXCR1). Using the in vitro transwell system, we demonstrate that TIL cells preferentially migrate toward melanoma and that endogenously expressing CXCR1 TIL cells are significantly enriched among the migrating lymphocytes. The role of the chemokines CXCL1 and CXCL8 is demonstrated by partial abrogation of this enrichment with anti-CXCL1 and anti-CXCL8 neutralizing antibodies. The role of the chemokine receptor CXCR1 is validated by the enhanced migration of CXCR1-engineered TIL cells toward melanoma or recombinant CXCL8. Cytotoxicity and IFNγ secretion activity are unaltered by CXCR1 expression profile. Taken together, these results mark CXCR1 as a candidate for genetic manipulations to enhance trafficking of adoptively transferred T cells. This approach is complimentary and potentially synergistic with other genetic strategies designed to enhance anti-tumor potency.
authors.affiliation: The Ella Institute for Melanoma Research and Treatment, Cancer Research Center, Sheba Medical Center, 52621 Ramat Gan, Tel Hashomer, Israel.
authors.forename: Sivan
authors.initials: S
authors.lastname: Sapoznik
authors.forename: Rona
authors.initials: R
authors.lastname: Ortenberg
authors.forename: Gilli
authors.initials: G
authors.lastname: Galore-Haskel
authors.forename: Stav
authors.initials: S
authors.lastname: Kozlovski
authors.forename: Daphna
authors.initials: D
authors.lastname: Levy
authors.forename: Camila
authors.initials: C
authors.lastname: Avivi
authors.forename: Iris
authors.initials: I
authors.lastname: Barshack
authors.forename: Cyrille J
authors.initials: CJ
authors.lastname: Cohen
authors.forename: Michal J
authors.initials: MJ
authors.lastname: Besser
authors.forename: Jacob
authors.initials: J
authors.lastname: Schachter
authors.forename: Gal
authors.initials: G
authors.lastname: Markel
mesh_terms: D057134:Antibodies, Neutralizing / Q000276:immunology / Q000494:pharmacology; D002465:Cell Movement / Q000276:immunology*; D018925:Chemokines / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008545:Melanoma / Q000276:immunology / Q000628:therapy*; D023062:Receptors, Interleukin-8A / Q000037:antagonists & inhibitors / Q000276:immunology*; D012878:Skin Neoplasms / Q000276:immunology / Q000628:therapy*; D014407:Tumor Cells, Cultured
chemical_list: D057134:Antibodies, Neutralizing; D018925:Chemokines; D023062:Receptors, Interleukin-8A