Supplementation of l-arginine boosts the therapeutic efficacy of anticancer chemoimmunotherapy

Cancer Sci. 2020 Jul;111(7):2248-2258. doi: 10.1111/cas.14490. Epub 2020 Jun 12.


Myeloid-derived suppressor cells (MDSCs) play a crucial role in immunosuppression in tumor-bearing hosts. MDSCs express arginase-I and indoleamine 2,3-dioxygenase; they suppress T-cell function by reducing the levels of l-arginine and l-tryptophan, respectively. We examined the anticancer effects of supplementation of these amino acids in CT26 colon carcinoma-bearing mice. Oral supplementation of l-arginine or l-tryptophan (30 mg/mouse) did not affect tumor growth, whereas oral supplementation of d-arginine was lethal. Supplementation of l-arginine showed a tendency to augment the efficacy of cyclophosphamide (CP). CP reduced the proportions of granulocytic MDSCs and increased the proportions of monocytic MDSCs in the spleen and tumor tissues of CT26-bearing mice. l-Arginine supplementation alone did not affect the MDSC subsets. CP treatment tended to reduce the plasma levels of l-arginine in CT26-bearing mice and significantly increased the number of tumor-infiltrating CD8+ T cells. In addition, l-arginine supplementation significantly increased the proportions of tumor peptide-specific CD8+ T cells in draining lymph nodes. Importantly, additional supplementation of l-arginine significantly increased the number of cured mice that were treated with CP and anti-PD-1 antibody. Totally, l-arginine supplementation shows promise for boosting the therapeutic efficacy of chemoimmunotherapy.

Keywords: MDSC; T cells; arginase-I; chemoimmunotherapy; l-arginine.

MeSH terms

  • Amino Acids / blood
  • Animals
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Antineoplastic Agents, Immunological / pharmacology*
  • Arginine / administration & dosage*
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclophosphamide / pharmacology
  • Dietary Supplements*
  • Dose-Response Relationship, Drug
  • Drug Synergism
  • Female
  • Flow Cytometry
  • Mice
  • Myeloid-Derived Suppressor Cells / drug effects
  • Myeloid-Derived Suppressor Cells / immunology
  • Myeloid-Derived Suppressor Cells / metabolism
  • Neoplasms / drug therapy
  • Neoplasms / immunology
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • T-Lymphocyte Subsets / drug effects
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism


  • Amino Acids
  • Antineoplastic Agents
  • Antineoplastic Agents, Immunological
  • Cyclophosphamide
  • Arginine