Rapamycin Impairs Antitumor CD8+ T-cell Responses and Vaccine-Induced Tumor Eradication

Cancer Res. 2015 Aug 15;75(16):3279-91. doi: 10.1158/0008-5472.CAN-15-0454. Epub 2015 Jun 29.

Abstract

The metabolic sensor mTOR broadly regulates cell growth and division in cancer cells, leading to a significant focus on studies of rapamycin and its analogues as candidate anticancer drugs. However, mTOR inhibitors have failed to produce useful clinical efficacy, potentially because mTOR is also critical in T cells implicated in immunosurveillance. Indeed, recent studies using rapamycin have demonstrated the important role of mTOR in differentiation and induction of the CD8+ memory in T-cell responses associated with antitumor properties. In this study, we demonstrate that rapamycin harms antitumor immune responses mediated by T cells in the setting of cancer vaccine therapy. Specifically, we analyzed how rapamycin affects the antitumor efficacy of a human papilloma virus E7 peptide vaccine (CyaA-E7) capable of eradicating tumors in the TC-1 mouse model of cervical cancer. In animals vaccinated with CyaA-E7, rapamycin administration completely abolished recruitment of CD8+ T cells into TC-1 tumors along with the ability of the vaccine to reduce infiltration of T regulatory cells and myeloid-derived suppressor cells. Moreover, rapamycin completely abolished vaccine-induced cytotoxic T-cell responses and therapeutic activity. Taken together, our results demonstrate the powerful effects of mTOR inhibition in abolishing T-cell-mediated antitumor immune responses essential for the therapeutic efficacy of cancer vaccines.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibiotics, Antineoplastic / immunology
  • Antibiotics, Antineoplastic / pharmacology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cancer Vaccines / administration & dosage
  • Cancer Vaccines / immunology*
  • Cell Line, Tumor
  • Disease Models, Animal
  • Female
  • Flow Cytometry
  • Humans
  • Mice, Inbred C57BL
  • Myeloid Cells / drug effects
  • Myeloid Cells / immunology
  • Myeloid Cells / metabolism
  • Neoplasms / immunology*
  • Neoplasms / metabolism
  • Neoplasms / prevention & control
  • Papillomavirus E7 Proteins / immunology
  • Sirolimus / immunology*
  • Sirolimus / pharmacology
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / metabolism
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / immunology
  • TOR Serine-Threonine Kinases / metabolism
  • Tumor Burden / drug effects
  • Tumor Burden / immunology

Substances

  • Antibiotics, Antineoplastic
  • Cancer Vaccines
  • Papillomavirus E7 Proteins
  • TOR Serine-Threonine Kinases
  • mTOR protein, mouse
  • Sirolimus