Anti-tumor effects of anti-PD-1 antibody, pembrolizumab, in humanized NSG PDX mice xenografted with dedifferentiated liposarcoma

Cancer Lett. 2020 May 28;478:56-69. doi: 10.1016/j.canlet.2020.02.042. Epub 2020 Mar 4.

Abstract

The efficacy of an immune checkpoint blockade has been demonstrated against various types of cancer, but its suitability has not been fully proven for therapies specifically targeting sarcoma. We conducted a pan-cancer tumor data analysis to identify key immune-related variables strongly associated with sarcoma prognosis, and we explored whether these expected factors are functionally correlated with anti-PD-1 therapy in humanized (Hu) NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice xenografted with dedifferentiated liposarcoma (DDLPS). We found that an abundance of hCD8+ T cells and hNK cells was functionally associated with anti-PD-1 effects in the Hu-NSG DDLPS mice. Phenotypically, these cells were shown to be hCD8+IFNγ+, hCD8+PD-1+, hCD8+Ki-67+, hCD56+IFNγ+, hCD56+PD-1+, and hCD56+Ki-67+ cells and were enriched in splenocytes and tumor-infiltrating lymphocytes (TILs) of Hu-NSG DDLPS mice treated with anti-PD-1 antibody. Moreover, a considerable increase in activated hCD56+NKp46+NKG2D+ NK cells was also detected. Our findings suggest that hCD8+ T and hNK subsets play a pivotal role in anti-DDLPS tumor effects of anti-PD-1 therapy. The results provide clinical reference for advanced anti-PD-1 therapy targeting sarcoma tumors including DDLPS.

Keywords: Anti-PD-1 antibody; Dedifferentiated liposarcoma; Humanized mouse model; Immunotherapy; Patient-derived xenograft.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Monoclonal, Humanized / administration & dosage*
  • Antibodies, Monoclonal, Humanized / pharmacology
  • CD8-Positive T-Lymphocytes / metabolism*
  • Cell Line, Tumor
  • Female
  • Humans
  • Killer Cells, Natural / drug effects
  • Killer Cells, Natural / metabolism*
  • Liposarcoma / drug therapy*
  • Liposarcoma / immunology
  • Liposarcoma / pathology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Middle Aged
  • Prognosis
  • Retroperitoneal Neoplasms / drug therapy*
  • Retroperitoneal Neoplasms / immunology
  • Retroperitoneal Neoplasms / pathology
  • Treatment Outcome
  • Tumor Microenvironment / drug effects
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Monoclonal, Humanized
  • pembrolizumab

Supplementary concepts

  • Retroperitoneal liposarcoma