Abstract
BackgroundImmune cells in the tumor microenvironment have prognostic value. In preclinical models, recruitment and infiltration of these cells depends on immune cell homing (ICH) genes such as chemokines, cell adhesion molecules, and integrins. We hypothesized ICH ligands CXCL9-11 and CCL2-5 would be associated with intratumoral T-cells, while CXCL13 would be more associated with B-cell infiltrates.MethodsSamples of human melanoma were submitted for gene expression analysis and immune cells identified by immunohistochemistry. Associations between the two were evaluated with unsupervised hierarchical clustering using correlation matrices from Spearman rank tests. Univariate analysis performed Mann–Whitney tests.ResultsFor 119 melanoma specimens, analysis of 78 ICH genes revealed association among genes with nonspecific increase of multiple immune cell subsets: CD45+, CD8+ and CD4+ T-cells, CD20+ B-cells, CD138+ plasma cells, and CD56+ NK-cells. ICH genes most associated with these infiltrates included ITGB2, ITGAL, CCL19, CXCL13, plus receptor/ligand pairs CXCL9 and CXCL10 with CXCR3; CCL4 and CCL5 with CCR5. This top ICH gene expression signature was also associated with genes representing immune-activation and effector function. In contrast, CD163+ M2-macrophages was weakly associated with a different ICH gene signature.ConclusionThese data do not support our hypothesis that each immune cell subset is uniquely associated with specific ICH genes. Instead, a larger set of ICH genes identifies melanomas with concordant infiltration of B-cell and T-cell lineages, while CD163+ M2-macrophage infiltration suggesting alternate mechanisms for their recruitment. Future studies should explore the extent ICH gene signature contributes to tertiary lymphoid structures or cross-talk between homing pathways.
Highlights
Immune cells in the tumor microenvironment have prognostic value
A group of immune cell homing genes is associated with Immunotype Score A total of 119 tumor specimens were included in the study that had both immune cell populations by IHC and gene expression data from the same formalinfixed paraffin-embedded (FFPE) block
The Immunotype Score is a continuous variable from 1.0 to 3.0 and used to categorize these values into Immunotype Groups, which are associated with survival: Immunotype A tumors have few or no infiltrating immune cells (Immunotype Score < 1.75), Immunotype B tumors have immune infiltrates that are limited to perivascular regions (Immunotype Score between 1.75–2.4), and Immunotype C tumors have diffuse immune cell infiltrates (Immunotype Score > 2.4) [5]
Summary
Immune cells in the tumor microenvironment have prognostic value. In preclinical models, recruitment and infiltration of these cells depends on immune cell homing (ICH) genes such as chemokines, cell adhesion molecules, and integrins. The density, location, and function of immune cells in the tumor microenvironment (TME), especially CD8+ T cells, are prognostic in melanoma [1,2,3,4,5,6] and other cancers [7,8,9], and can predict patient responses to immunomodulating therapies [10,11,12,13]. Individual immune cells can infiltrate among tumor cells, but they can organize into tertiary lymphoid structures (TLS) in tumor deposits and at their periphery [14]. The varied distributions of immune cell subsets among melanomas from different patients raise questions about the factors that mediate infiltration of these and other immune subsets
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