Generation of Tumor-Reactive T Cells by Co-culture of Peripheral Blood Lymphocytes and Tumor Organoids

Cell. 2018 Sep 6;174(6):1586-1598.e12. doi: 10.1016/j.cell.2018.07.009. Epub 2018 Aug 9.

Abstract

Cancer immunotherapies have shown substantial clinical activity for a subset of patients with epithelial cancers. Still, technological platforms to study cancer T-cell interactions for individual patients and understand determinants of responsiveness are presently lacking. Here, we establish and validate a platform to induce and analyze tumor-specific T cell responses to epithelial cancers in a personalized manner. We demonstrate that co-cultures of autologous tumor organoids and peripheral blood lymphocytes can be used to enrich tumor-reactive T cells from peripheral blood of patients with mismatch repair-deficient colorectal cancer and non-small-cell lung cancer. Furthermore, we demonstrate that these T cells can be used to assess the efficiency of killing of matched tumor organoids. This platform provides an unbiased strategy for the isolation of tumor-reactive T cells and provides a means by which to assess the sensitivity of tumor cells to T cell-mediated attack at the level of the individual patient.

Keywords: T cell; adoptive cell transfer; colorectal cancer; immune checkpoint blockade; immunotherapy; microsatellite instable; mismatch repair deficient; non-small cell lung cancer; organoids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Culture Techniques
  • Coculture Techniques
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology
  • Female
  • Humans
  • In Vitro Techniques
  • Interferon-gamma / pharmacology
  • Leukocytes, Mononuclear / cytology*
  • Leukocytes, Mononuclear / metabolism
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lymphocyte Activation / drug effects
  • Male
  • Middle Aged
  • T-Lymphocytes / cytology
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology*
  • Tumor Cells, Cultured

Substances

  • Interferon-gamma