Characterization of chemokines and adhesion molecules associated with T cell presence in tertiary lymphoid structures in human lung cancer

Cancer Res. 2011 Oct 15;71(20):6391-9. doi: 10.1158/0008-5472.CAN-11-0952. Epub 2011 Sep 7.

Abstract

De novo formation of tertiary lymphoid structures (TLS) has been described in lung cancers. Intratumoral TLS seem to be functional and are associated with a long-term survival for lung cancer patients, suggesting that they represent an activation site for tumor-specific T cells. Here, we characterized T-cell recruitment to TLS in human lung cancer to identify the adhesion molecules and chemoattractants orchestrating this migration. We found that most TLS T cells were CD62L+ and mainly of CD4+ memory phenotype, but naive T cells were highly enriched in these structures as compared with the rest of the tumor. A specific gene expression signature associated with T cell presence was identified in TLS, which included chemokines (CCL19, CCL21, CXCL13, CCL17, CCL22, and IL16), adhesion molecules (ICAM-2, ICAM-3, VCAM-1, and MAdCAM-1) and integrins (alphaL, alpha4, and alphaD). The presence of the corresponding receptors on TLS T cells was confirmed. Intratumoral PNAd+ high endothelial venules also were exclusively associated with TLS and colocalized with CD62L+ lymphocytes. Together, these data bring new insights into the T-cell recruitment to intratumoral TLS and suggest that blood T cell enter into TLS via high endothelial venules, which represent a new gateway for T cells to the tumor. Findings identify the molecules that mediate migration of tumor-specific T cells into TLS where T cell priming occurs, suggesting new strategies to enhance the efficacy of cancer immunotherapies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / immunology
  • Adenocarcinoma / metabolism*
  • Adenocarcinoma of Lung
  • Adult
  • Aged
  • Aged, 80 and over
  • Cell Adhesion Molecules / immunology
  • Cell Adhesion Molecules / metabolism*
  • Cell Movement / immunology
  • Cell Movement / physiology
  • Chemokines / immunology
  • Chemokines / metabolism*
  • Female
  • Gene Expression Profiling
  • Humans
  • Integrins / immunology
  • Integrins / metabolism*
  • Lung Neoplasms / immunology
  • Lung Neoplasms / metabolism*
  • Lymphoid Tissue / immunology
  • Lymphoid Tissue / metabolism*
  • Male
  • Middle Aged
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*

Substances

  • Cell Adhesion Molecules
  • Chemokines
  • Integrins