A retinoic acid--rich tumor microenvironment provides clonal survival cues for tumor-specific CD8(+) T cells

Cancer Res. 2012 Oct 15;72(20):5230-9. doi: 10.1158/0008-5472.CAN-12-1727. Epub 2012 Aug 17.

Abstract

While vitamin A has been implicated in host resistance to infectious disease, little is known about the role of vitamin A and its active metabolite, retinoic acid (RA) in host defenses against cancer. Here, we show that local RA production within the tumor microenvironment (TME) is increased up to 5-fold as compared with naïve surrounding tissue, with a commensurate increase in RA signaling to regionally infiltrating tumor-reactive T cells. Conditional disruption of RA signaling in CD8(+) T cells using a dominant negative retinoic acid receptor α (dnRARα) established that RA signaling is required for tumor-specific CD8(+) T-cell expansion/accumulation and protective antitumor immunity. In vivo analysis of antigen-specific CD8(+) T-cell responses revealed that early T-cell expansion was RA-independent; however, late T-cell expansion and clonal accumulation was suppressed strongly in the absence of RA signaling. Our findings indicate that RA function is essential for the survival of tumor-reactive CD8(+) T cells within the TME.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes / cytology*
  • Cell Survival*
  • Enzyme-Linked Immunosorbent Assay
  • Mice
  • Mice, Inbred C57BL
  • Signal Transduction
  • Tretinoin / metabolism*
  • Tumor Microenvironment*

Substances

  • Tretinoin