TCR Repertoire Analysis Reveals Mobilization of Novel CD8+ T Cell Clones Into the Cancer-Immunity Cycle Following Anti-CD4 Antibody Administration

Front Immunol. 2019 Jan 24;9:3185. doi: 10.3389/fimmu.2018.03185. eCollection 2018.

Abstract

Depletion of CD4+ cells using an anti-CD4 monoclonal antibody (anti-CD4 mAb) induces the expansion of tumor-reactive CD8+ T cells and strong antitumor effects in several murine tumor models. However, it is not known whether the anti-CD4 mAb treatment activates a particular or a broad spectrum of tumor-reactive CD8+ T cell clones. To investigate the changes in the TCR repertoire induced by the anti-CD4 mAb treatment, we performed unbiased high-throughput TCR sequencing in a B16F10 mouse subcutaneous melanoma model. By Inter-Organ Clone Tracking analysis, we demonstrated that anti-CD4 mAb treatment increased the diversity and combined frequency of CD8+ T cell clones that overlapped among the tumor, draining lymph node (dLN), and peripheral blood repertoires. Interestingly, the anti-CD4 mAb treatment-induced expansion of overlapping clones occurred mainly in the dLN rather than in the tumor. Overall, the Inter-Organ Clone Tracking analysis revealed that anti-CD4 mAb treatment enhances the mobilization of a wide variety of tumor-reactive CD8+ T cell clones into the Cancer-Immunity Cycle and thus induces a robust antitumor immune response in mice.

Keywords: Cancer-Immunity Cycle; Inter-Organ Clone Tracking; TCR repertoire; anti-CD4 mAb; immune checkpoint inhibitor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal / immunology
  • Antibodies, Monoclonal / pharmacology
  • Antineoplastic Agents, Immunological / immunology
  • Antineoplastic Agents, Immunological / pharmacology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism*
  • Clonal Evolution / genetics
  • Clonal Evolution / immunology*
  • Disease Models, Animal
  • Female
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / genetics
  • Lymphocyte Activation / immunology*
  • Lymphocytes, Tumor-Infiltrating / immunology
  • Lymphocytes, Tumor-Infiltrating / metabolism
  • Melanoma, Experimental
  • Mice
  • Mice, Transgenic
  • Neoplasms / drug therapy
  • Neoplasms / immunology*
  • Neoplasms / metabolism*
  • Neoplasms / pathology
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / metabolism*
  • Treatment Outcome

Substances

  • Antibodies, Monoclonal
  • Antineoplastic Agents, Immunological
  • Receptors, Antigen, T-Cell