CD8+ Tumor-Infiltrating T Cells Are Trapped in the Tumor-Dendritic Cell Network

Neoplasia. 2013 Jan;15(1):85-94. doi: 10.1593/neo.121572.

Abstract

Chemotherapy enhances the antitumor adaptive immune T cell response, but the immunosuppressive tumor environment often dominates, resulting in cancer relapse. Antigen-presenting cells such as tumor-associated macrophages (TAMs) and tumor dendritic cells (TuDCs) are the main protagonists of tumor-infiltrating lymphocyte (TIL) immunosuppression. TAMs have been widely investigated and are associated with poor prognosis, but the immunosuppressive activity of TuDCs is less well understood. We performed two-photon imaging of the tumor tissue to examine the spatiotemporal interactions between TILs and TuDCs after chemotherapy. In a strongly immunosuppressive murine tumor model, cyclophosphamide-mediated chemotherapy transiently enhanced the antitumor activity of adoptively transferred ovalbumin-specific CD8(+) T cell receptor transgenic T cells (OTI) but barely affected TuDC compartment within the tumor. Time lapse imaging of living tumor tissue showed that TuDCs are organized as a mesh with dynamic interconnections. Once infiltrated into the tumor parenchyma, OTI T cells make antigen-specific and long-lasting contacts with TuDCs. Extensive analysis of TIL infiltration on histologic section revealed that after chemotherapy the majority of OTI T cells interact with TuDCs and that infiltration is restricted to TuDC-rich areas. We propose that the TuDC network exerts antigen-dependent unproductive retention that trap T cells and limit their antitumor effectiveness.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens / immunology
  • CD8-Positive T-Lymphocytes / immunology*
  • Dendritic Cells / immunology*
  • Female
  • Immune Tolerance / immunology
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic / immunology
  • Receptors, Antigen, T-Cell / immunology
  • T-Lymphocytes, Cytotoxic / immunology*

Substances

  • Antigens
  • Receptors, Antigen, T-Cell