Critical Role for CD103(+)/CD141(+) Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma

Overview

Journal Cancer Cell

Publisher Cell Press

Specialty Oncology

Date 2016 Jul 19

PMID 27424807

Citations 532

Authors

Edward W Roberts

Miranda L Broz

Mikhail Binnewies

Mark B Headley

Amanda E Nelson

Denise M Wolf

Tsuneyasu Kaisho

Dusan Bogunovic

Nina Bhardwaj

Matthew F Krummel

Affiliations

Soon will be listed here.

Abstract

Intratumoral dendritic cells (DC) bearing CD103 in mice or CD141 in humans drive intratumoral CD8(+) T cell activation. Using multiple strategies, we identified a critical role for these DC in trafficking tumor antigen to lymph nodes (LN), resulting in both direct CD8(+) T cell stimulation and antigen hand-off to resident myeloid cells. These effects all required CCR7. Live imaging demonstrated direct presentation to T cells in LN, and CCR7 loss specifically in these cells resulted in defective LN T cell priming and increased tumor outgrowth. CCR7 expression levels in human tumors correlate with signatures of CD141(+) DC, intratumoral T cells, and better clinical outcomes. This work identifies an ongoing pathway to T cell priming, which should be harnessed for tumor therapies.

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References

Indra A, Warot X, Brocard J, Bornert J, Xiao J, Chambon P . Temporally-controlled site-specific mutagenesis in the basal layer of the epidermis: comparison of the recombinase activity of the tamoxifen-inducible Cre-ER(T) and Cre-ER(T2) recombinases. Nucleic Acids Res. 1999; 27(22):4324-7. PMC: 148712. DOI: 10.1093/nar/27.22.4324. View

Pooley J, Heath W, Shortman K . Cutting edge: intravenous soluble antigen is presented to CD4 T cells by CD8- dendritic cells, but cross-presented to CD8 T cells by CD8+ dendritic cells. J Immunol. 2001; 166(9):5327-30. DOI: 10.4049/jimmunol.166.9.5327. View

Ruzankina Y, Pinzon-Guzman C, Asare A, Ong T, Pontano L, Cotsarelis G . Deletion of the developmentally essential gene ATR in adult mice leads to age-related phenotypes and stem cell loss. Cell Stem Cell. 2008; 1(1):113-126. PMC: 2920603. DOI: 10.1016/j.stem.2007.03.002. View

Allan R, Waithman J, Bedoui S, Jones C, Villadangos J, Zhan Y . Migratory dendritic cells transfer antigen to a lymph node-resident dendritic cell population for efficient CTL priming. Immunity. 2006; 25(1):153-62. DOI: 10.1016/j.immuni.2006.04.017. View

Sixt M, Kanazawa N, Selg M, Samson T, Roos G, Reinhardt D . The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity. 2005; 22(1):19-29. DOI: 10.1016/j.immuni.2004.11.013. View

den Bosch T, Koopmans A, Vaarwater J, van den Berg M, de Klein A, Verdijk R . Chemokine receptor CCR7 expression predicts poor outcome in uveal melanoma and relates to liver metastasis whereas expression of CXCR4 is not of clinical relevance. Invest Ophthalmol Vis Sci. 2013; 54(12):7354-61. DOI: 10.1167/iovs.13-12407. View

Dunn G, Old L, Schreiber R . The immunobiology of cancer immunosurveillance and immunoediting. Immunity. 2004; 21(2):137-48. DOI: 10.1016/j.immuni.2004.07.017. View

Curran M, Allison J . Tumor vaccines expressing flt3 ligand synergize with ctla-4 blockade to reject preimplanted tumors. Cancer Res. 2009; 69(19):7747-55. PMC: 2756314. DOI: 10.1158/0008-5472.CAN-08-3289. View

Eickhoff S, Brewitz A, Gerner M, Klauschen F, Komander K, Hemmi H . Robust Anti-viral Immunity Requires Multiple Distinct T Cell-Dendritic Cell Interactions. Cell. 2015; 162(6):1322-37. PMC: 4567961. DOI: 10.1016/j.cell.2015.08.004. View

10.

Bogunovic D, ONeill D, Belitskaya-Levy I, Vacic V, Yu Y, Adams S . Immune profile and mitotic index of metastatic melanoma lesions enhance clinical staging in predicting patient survival. Proc Natl Acad Sci U S A. 2009; 106(48):20429-34. PMC: 2787158. DOI: 10.1073/pnas.0905139106. View

11.

Asano K, Nabeyama A, Miyake Y, Qiu C, Kurita A, Tomura M . CD169-positive macrophages dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity. 2011; 34(1):85-95. DOI: 10.1016/j.immuni.2010.12.011. View

12.

Haniffa M, Shin A, Bigley V, McGovern N, Teo P, See P . Human tissues contain CD141hi cross-presenting dendritic cells with functional homology to mouse CD103+ nonlymphoid dendritic cells. Immunity. 2012; 37(1):60-73. PMC: 3476529. DOI: 10.1016/j.immuni.2012.04.012. View

13.

Pardoll D . The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012; 12(4):252-64. PMC: 4856023. DOI: 10.1038/nrc3239. View

14.

Gajewski T, Schreiber H, Fu Y . Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013; 14(10):1014-22. PMC: 4118725. DOI: 10.1038/ni.2703. View

15.

Engelhardt J, Boldajipour B, Beemiller P, Pandurangi P, Sorensen C, Werb Z . Marginating dendritic cells of the tumor microenvironment cross-present tumor antigens and stably engage tumor-specific T cells. Cancer Cell. 2012; 21(3):402-17. PMC: 3311997. DOI: 10.1016/j.ccr.2012.01.008. View

16.

Nakamura Y, Ishii J, Kondo A . Bright fluorescence monitoring system utilizing Zoanthus sp. green fluorescent protein (ZsGreen) for human G-protein-coupled receptor signaling in microbial yeast cells. PLoS One. 2013; 8(12):e82237. PMC: 3855394. DOI: 10.1371/journal.pone.0082237. View

17.

Vanneman M, Dranoff G . Combining immunotherapy and targeted therapies in cancer treatment. Nat Rev Cancer. 2012; 12(4):237-51. PMC: 3967236. DOI: 10.1038/nrc3237. View

18.

Edelson B, Kc W, Juang R, Kohyama M, Benoit L, Klekotka P . Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8alpha+ conventional dendritic cells. J Exp Med. 2010; 207(4):823-36. PMC: 2856032. DOI: 10.1084/jem.20091627. View

19.

Fidler I . Biological behavior of malignant melanoma cells correlated to their survival in vivo. Cancer Res. 1975; 35(1):218-24. View

20.

Kawakami Y, Eliyahu S, Delgado C, Robbins P, Sakaguchi K, Appella E . Identification of a human melanoma antigen recognized by tumor-infiltrating lymphocytes associated with in vivo tumor rejection. Proc Natl Acad Sci U S A. 1994; 91(14):6458-62. PMC: 44221. DOI: 10.1073/pnas.91.14.6458. View