Dual blockade of CXCL12-CXCR4 and PD-1-PD-L1 pathways prolongs survival of ovarian tumor-bearing mice by prevention of immunosuppression in the tumor microenvironment

FASEB J. 2019 May;33(5):6596-6608. doi: 10.1096/fj.201802067RR. Epub 2019 Feb 25.

Abstract

Blockade of immune-checkpoint programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 can enhance effector T-cell responses. However, the lack of response in many patients to checkpoint-inhibitor therapies emphasizes the need for combination immunotherapies to pursue maximal antitumor efficacy. We have previously demonstrated that antagonism of C-X-C chemokine receptor type 4 (CXCR4) by plerixafor (AMD3100) can decrease regulatory T (Treg)-cell intratumoral infiltration. Therefore, a combination of these 2 therapies might increase antitumor effects. Here, we evaluated the antitumor efficacy of AMD3100 and anti-PD-1 (αPD-1) antibody alone or in combination in an immunocompetent syngeneic mouse model of ovarian cancer. We found that AMD3100, a highly specific CXCR4 antagonist, directly down-regulated the expression of both C-X-C motif chemokine 12 (CXCL12) and CXCR4 in vitro and in vivo in tumor cells. AMD3100 and αPD-1 significantly inhibited tumor growth and prolonged the survival of tumor-bearing mice when given as monotherapy. Combination of these 2 agents significantly enhanced antitumor effects compared with single-agent administration. Benefits of tumor control and animal survival were associated with immunomodulation mediated by these 2 agents, which were characterized by increased effector T-cell infiltration, increased effector T-cell function, and increased memory T cells in tumor microenvironment. Intratumoral Treg cells were decreased, and conversion of Treg cells into T helper cells was increased by AMD3100 treatment. Intratumoral myeloid-derived suppressor cells were decreased by the combined treatment, which was associated with decreased IL-10 and IL-6 in the ascites. Also, the combination therapy decreased suppressive leukocytes and facilitated M2-to-M1 macrophage polarization in the tumor. These results suggest that AMD3100 could be used to target the CXCR4-CXCL12 axis to inhibit tumor growth and prevent multifaceted immunosuppression alone or in combination with αPD-1 in ovarian cancer, which could be clinically relevant to patients with this disease.-Zeng, Y., Li, B., Liang, Y., Reeves, P. M., Qu, X., Ran, C., Liu, Q., Callahan, M. V., Sluder, A. E., Gelfand, J. A., Chen, H., Poznansky, M. C. Dual blockade of CXCL12-CXCR4 and PD-1-PD-L1 pathways prolongs survival of ovarian tumor-bearing mice by prevention of immunosuppression in the tumor microenvironment.

Keywords: CXCR4 antagonist; combination immunotherapy; immune checkpoint inhibitor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen* / antagonists & inhibitors
  • B7-H1 Antigen* / immunology
  • Cell Line, Tumor
  • Chemokine CXCL12* / antagonists & inhibitors
  • Chemokine CXCL12* / immunology
  • Female
  • Heterocyclic Compounds / pharmacology*
  • Immune Tolerance / drug effects*
  • Mice
  • Neoplasm Proteins* / antagonists & inhibitors
  • Neoplasm Proteins* / immunology
  • Ovarian Neoplasms* / drug therapy
  • Ovarian Neoplasms* / immunology
  • Ovarian Neoplasms* / pathology
  • Programmed Cell Death 1 Receptor* / antagonists & inhibitors
  • Programmed Cell Death 1 Receptor* / immunology
  • Receptors, CXCR4* / antagonists & inhibitors
  • Receptors, CXCR4* / immunology
  • Signal Transduction* / drug effects
  • Signal Transduction* / immunology
  • Tumor Microenvironment* / drug effects
  • Tumor Microenvironment* / immunology

Substances

  • B7-H1 Antigen
  • CXCR4 protein, mouse
  • Cd274 protein, mouse
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • Heterocyclic Compounds
  • Neoplasm Proteins
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, CXCR4
  • plerixafor