Tumor-specific CD4+ T cells maintain effector and memory tumor-specific CD8+ T cells

Eur J Immunol. 2014 Jan;44(1):69-79. doi: 10.1002/eji.201343718. Epub 2013 Nov 21.


Immunotherapies that augment antitumor T cells have had recent success for treating patients with cancer. Here we examined whether tumor-specific CD4(+) T cells enhance CD8(+) T-cell adoptive immunotherapy in a lymphopenic environment. Our model employed physiological doses of tyrosinase-related protein 1-specific CD4(+) transgenic T cells-CD4(+) T cells and pmel-CD8(+) T cells that when transferred individually were subtherapeutic; however, when transferred together provided significant (p ≤ 0.001) therapeutic efficacy. Therapeutic efficacy correlated with increased numbers of effector and memory CD8(+) T cells with tumor-specific cytokine expression. When combined with CD4(+) T cells, transfer of total (naïve and effector) or effector CD8(+) T cells were highly effective, suggesting CD4(+) T cells can help mediate therapeutic effects by maintaining function of activated CD8(+) T cells. In addition, CD4(+) T cells had a pronounced effect in the early posttransfer period, as their elimination within the first 3 days significantly (p < 0.001) reduced therapeutic efficacy. The CD8(+) T cells recovered from mice treated with both CD8(+) and CD4(+) T cells had decreased expression of PD-1 and PD-1-blockade enhanced the therapeutic efficacy of pmel-CD8 alone, suggesting that CD4(+) T cells help reduce CD8(+) T-cell exhaustion. These data support combining immunotherapies that elicit both tumor-specific CD4(+) and CD8(+) T cells for treatment of patients with cancer.

Keywords: CD4+ T-cell help; Cancer immunotherapy; Metastatic melanoma; PD-1; T cell.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / transplantation
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / transplantation
  • Cancer Vaccines / immunology
  • Cell Communication
  • Cellular Microenvironment
  • Cytotoxicity, Immunologic
  • Female
  • Immunologic Memory
  • Immunotherapy, Adoptive / methods*
  • Immunotherapy, Adoptive / trends
  • Male
  • Melanoma, Experimental / immunology*
  • Melanoma, Experimental / therapy*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Mice, Knockout
  • Mice, Transgenic
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism


  • Antigens, Neoplasm
  • Cancer Vaccines
  • Membrane Glycoproteins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Oxidoreductases
  • Tyrp1 protein, mouse