Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma
Nicolas Jacquelot, … , Alexander Eggermont, Laurence Zitvogel
Nicolas Jacquelot, … , Alexander Eggermont, Laurence Zitvogel
Published February 8, 2016
Citation Information: J Clin Invest. 2016;126(3):921-937. https://doi.org/10.1172/JCI80071.
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Research Article Oncology

Chemokine receptor patterns in lymphocytes mirror metastatic spreading in melanoma

Abstract

Melanoma prognosis is dictated by tumor-infiltrating lymphocytes, the migratory and functional behavior of which is guided by chemokine or cytokine gradients. Here, we retrospectively analyzed the expression patterns of 9 homing receptors (CCR/CXCR) in naive and memory CD4+ and CD8+ T lymphocytes in 57 patients with metastatic melanoma (MMel) with various sites of metastases to evaluate whether T cell CCR/CXCR expression correlates with intratumoral accumulation, metastatic progression, and/or overall survival (OS). Homing receptor expression on lymphocytes strongly correlated with MMel dissemination. Loss of CCR6 or CXCR3, but not cutaneous lymphocyte antigen (CLA), on circulating T cell subsets was associated with skin or lymph node metastases, loss of CXCR4, CXCR5, and CCR9 corresponded with lung involvement, and a rise in CCR10 or CD103 was associated with widespread dissemination. High frequencies of CD8+CCR9+ naive T cells correlated with prolonged OS, while neutralizing the CCR9/CCL25 axis in mice stimulated tumor progression. The expansion of CLA-expressing effector memory CD8+ T cells in response to a single administration of CTLA4 blockade predicted disease control at 3 months in 47 patients with MMel. Thus, specific CCR/CXCR expression patterns on circulating T lymphocytes may guide potential diagnostic and therapeutic approaches.

Authors

Nicolas Jacquelot, David P. Enot, Caroline Flament, Nadège Vimond, Carolin Blattner, Jonathan M. Pitt, Takahiro Yamazaki, María Paula Roberti, Romain Daillère, Marie Vétizou, Vichnou Poirier-Colame, Michaëla Semeraro, Anne Caignard, Craig L. Slingluff Jr., Federica Sallusto, Sylvie Rusakiewicz, Benjamin Weide, Aurélien Marabelle, Holbrook Kohrt, Stéphane Dalle, Andréa Cavalcanti, Guido Kroemer, Anna Maria Di Giacomo, Michele Maio, Phillip Wong, Jianda Yuan, Jedd Wolchok, Viktor Umansky, Alexander Eggermont, Laurence Zitvogel

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Figure 7

Neutralizing CCL25 or CXCR3 independently impacted tumor progression.

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Neutralizing CCL25 or CXCR3 independently impacted tumor progression. (A...
(A and B) Naive and memory CD4+ and CD8+ T cells from RET-induced mouse melanomas, metastatic LNs, and spleens analyzed by multicolor flow cytometry. TNs were characterized as CD4+CD45RB+ and CD8+CD44lo, central memory (CM), CD4+CD45RB–CD62L+, and CD8+CD44hiCD62L+ cells, while effector memory (EM) cells were defined as CD4+CD45RB–CD62L– and CD8+CD44hiCD62L– cells. Cumulative data showing expression levels of CCR9 and CXCR3 are depicted as percentages of the respective cell subset within live total CD4+ or CD8+ T cells from 3 independent experiments in the 3 locations. (C) Frequencies of CD8+CD44loCCR9+ T cells within total live CD8+ T cells in skin lesions in relation to the skin tumor weight (n = 11, 3 independent experiments). (D) Ex vivo explanted MCA205 sarcoma tumor as well as gut explants were dosed for CCL25 and normalized to total protein content. (E) MCA205 cells were inoculated in C57BL/6 mice that were concomitantly treated with i.p. administration of anti-CCL25 Ab, positive control anti-CXCR3 Ab, and their respective isotype controls (Iso) (5 injections, every 3 days). Tumor sizes were monitored until sacrifice and are depicted at day 6 (left panel) and day 17 (right panel) from 2 independent experiments. (F and G) Flow cytometric monitoring of CD4+ and CD8+ T cells in tumor beds (left panel) and tumor-dLNs (right panel) after neutralization of CCL25 or CXCR3 at the time of sacrifice (day 13). Each point represents 1 specimen, and the total number is indicated for all subpopulations studied. Statistical analyses were performed by beta regression (A and B), linear mixed-effects (D, F, and G), and linear (D and E) modeling, or by Spearman’s test. Raw P values are indicated.