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.
View: Text | PDF
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

×

Figure 2

Nonhierarchical clustering of the expression of CCR and CXCR studied in circulating T cells from patients with MMel after normalization to HV-related values.

Options: View larger image (or click on image) Download as PowerPoint
Nonhierarchical clustering of the expression of CCR and CXCR studied in ...
(A) Heatmap representing 62 markers that were found significantly altered among patient groups at an FDR below 0.1. Each cell depicts the fold change between the metastatic group and a cohort of HVs (n = 26): red indicates an increase and green a decrease in marker levels compared with those in the reference population. The dendrogram classifies 57 patients (featured according to their metastatic dissemination patterns at diagnosis) for CCR and CXCR expression on all 4 subsets of CD4+ and CD8+ T lymphocytes (featured for each marker), highlighting that most chemokine receptor families segregated according to metastatic spreading (summarized at the bottom), with a decrease (green) or increase (red) in peripheral blood levels compared with those in HVs. From left to right: primary sites of invasion (skin and LNs), followed by additional locations of metastatic spreading (such as to lungs and other distant organs). As for liver metastases, CD103 upregulation may constitute a hallmark (Supplemental Figure 4). Pts, patients. (B–D) log2-based fold changes (and 95% CI) in parameter levels between the metastatic groups and the HV cohort for the 62 markers found altered among the patient groups. Markers that were significantly associated with patient prognosis (detailed in the subsequent figures) are highlighted in red. Asterisks indicate significance (as compared with HVs), after adjusting for multiple tests: †P < 0.1, *P < 0.05, **P < 0.01, and ***P < 0.001, by beta regression.