title: Therapeutic Peptide Vaccine-Induced CD8 T Cells Strongly Modulate Intratumoral Macrophages Required for Tumor Regression.
abstract: Abundant macrophage infiltration of solid cancers commonly correlates with poor prognosis. Tumor-promoting functions of macrophages include angiogenesis, metastasis formation, and suppression of Th1-type immune responses. Here, we show that successful treatment of cervical carcinoma in mouse models with synthetic long peptide (SLP) vaccines induced influx of cytokine-producing CD8 T cells that strongly altered the numbers and phenotype of intratumoral macrophages. On the basis of the expression of CD11b, CD11c, F4/80, Ly6C, Ly6G, and MHC II, we identified four myeloid subpopulations that increased in numbers from 2.0-fold to 8.7-fold in regressing tumors. These changes of the intratumoral myeloid composition coincided with macrophage recruitment by chemokines, including CCL2 and CCL5, and were completely dependent on a vaccine-induced influx of tumor-specific CD8 T cells. CD4 T cells were dispensable. Incubation of tumor cells with T cell-derived IFNγ and TNFα recapitulated the chemokine profile observed in vivo, confirming the capacity of antitumor CD8 T cells to mediate macrophage infiltration of tumors. Strikingly, complete regressions of large established tumors depended on the tumor-infiltrating macrophages that were induced by this immunotherapy, because a small-molecule drug inhibitor targeting CSF-1R diminished the number of intratumoral macrophages and abrogated the complete remissions. Survival rates after therapeutic SLP vaccination deteriorated in the presence of CSF-1R blockers. Together, these results show that therapeutic peptide vaccination could induce cytokine-producing T cells with strong macrophage-skewing capacity necessary for tumor shrinkage, and suggest that the development of macrophage-polarizing, rather than macrophage-depleting, agents is warranted.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Tetje C
authors.initials: TC
authors.lastname: van der Sluis
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Marjolein
authors.initials: M
authors.lastname: Sluijter
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Suzanne
authors.initials: S
authors.lastname: van Duikeren
authors.affiliation: Plexxikon Inc., Berkeley, California.
authors.forename: Brian L
authors.initials: BL
authors.lastname: West
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. ISA Pharmaceuticals, Leiden, the Netherlands.
authors.forename: Cornelis J M
authors.initials: CJ
authors.lastname: Melief
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Ramon
authors.initials: R
authors.lastname: Arens
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Sjoerd H
authors.initials: SH
authors.lastname: van der Burg
authors.affiliation: Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands. T.van_Hall@lumc.nl.
authors.forename: Thorbald
authors.initials: T
authors.lastname: van Hall
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D002465:Cell Movement / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000187:drug effects; D010051:Ovarian Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology; D022223:Vaccines, Subunit / Q000276:immunology / Q000627:therapeutic use
chemical_list: D000631:Aminopyridines; D019496:Cancer Vaccines; D018925:Chemokines; D011758:Pyrroles; D022223:Vaccines, Subunit; C000600259:pexidartinib; D011505:Protein-Tyrosine Kinases