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Cancer Immunol Res. 2015 Sep;3(9):1042-51. doi: 10.1158/2326-6066.CIR-15-0052. Epub 2015 Apr 17.

Therapeutic Peptide Vaccine-Induced CD8 T Cells Strongly Modulate Intratumoral Macrophages Required for Tumor Regression.

Author information

1
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands.
2
Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands.
3
Plexxikon Inc., Berkeley, California.
4
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, the Netherlands. ISA Pharmaceuticals, Leiden, the Netherlands.
5
Department of Clinical Oncology, Leiden University Medical Center, Leiden, the Netherlands. T.van_Hall@lumc.nl.

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.

PMID:
25888578
DOI:
10.1158/2326-6066.CIR-15-0052
[Indexed for MEDLINE]
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