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 3

LN metastases–associated chemokine receptor CCR6 and CXCR3 expression, function, and survival.

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LN metastases–associated chemokine receptor CCR6 and CXCR3 expression, f...
(A) CCR6 expression on CD8+ TEMs in HVs and in patients presenting with only cutaneous and LN metastases (Cut + LN), additional lung involvement, disseminated disease (Multi), and in those with metastases in lungs and other distant organs (Multi + lung) at the time of inclusion in 1 of the 3 protocols described in the Methods. (B) Match-paired comparison of CCR6 expression (performed by flow cytometry on fresh tissues) in all CD8+ T cell subsets from blood (B) and tumors (T) at the time of surgery in the prospective cohort of 20 patients with MMel. (C) CCR6+CD8+ T cell cytokine profile. Flow cytometry–guided sorting based on CCR6 expression in blood CD8+ T cells from 1 representative patient (out of 2 patients, yielding similar results; data represent the mean from duplicate wells) to analyze cytokine release after a 40-hour CD3/CD28 mAb–driven stimulation. (D) Kaplan-Meier survival curves representing data from 57 MMel patients according to their proportions of circulating CCR6+CD8+ TEMs, segregated in tertiles. (E and F) Same as in A, showing expression of the CXCR3 subset on CD4 TCMs (E) and TEMs (F). (G) Same as in B, showing CXCR3 expression on CD4 T cell subsets. (H) Kaplan-Meier survival curves for 57 MMel patients according to the median of the proportions of circulating CXCR3+CD4+ TEMs. Each point represents 1 patient specimen, and the total number is indicated for all subpopulations studied. Statistical analyses were performed by beta regression (A, E, and F), linear mixed-effects (B and G), and Cox regression (D and H) modeling. Raw P values are indicated. LRT, likelihood ratio test.