Osteopontin blockade immunotherapy increases cytotoxic t lymphocyte lytic activity and suppresses colon tumor progression

John D. Klement, Dakota B. Poschel, Chunwan Lu, Alyssa D. Merting, Dafeng Yang, Priscilla S. Redd, Kebin Liu

Research output: Contribution to journalArticlepeer-review

Abstract

Human colorectal cancers are mostly microsatellite-stable with no response to anti-PD-1 blockade immunotherapy, necessitating the development of a new immunotherapy. Osteopontin (OPN) is elevated in human colorectal cancer and may function as an immune checkpoint. We aimed at elucidating the mechanism of action of OPN and determining the efficacy of OPN blockade immunotherapy in suppression of colon cancer. We report here that OPN is primarily expressed in tumor cells, myeloid cells, and innate lymphoid cells in human colorectal carcinoma. Spp1 knock out mice exhibit a high incidence and fast growth rate of carcinogen-induced tumors. Knocking out Spp1 in colon tumor cells increased tumor-specific CTL cytotoxicity in vitro and resulted in decreased tumor growth in vivo. The OPN protein level is elevated in the peripheral blood of tumor-bearing mice. We developed four OPN neutralization monoclonal antibodies based on their efficacy in blocking OPN inhibition of T cell activation. OPN clones 100D3 and 103D6 increased the efficacy of tumor-specific CTLs in killing colon tumor cells in vitro and suppressed colon tumor growth in tumor-bearing mice in vivo. Our data indicate that OPN blockade immunotherapy with 100D3 and 103D6 has great potential to be further developed for colorectal cancer immunotherapy and for rendering a colorectal cancer response to anti-PD-1 immunotherapy.

Original languageEnglish (US)
Article number1006
Pages (from-to)1-15
Number of pages15
JournalCancers
Volume13
Issue number5
DOIs
StatePublished - Mar 1 2021

Keywords

  • Cytotoxic T lymphocytes
  • Immune checkpoint
  • MSS
  • OPN neutralization
  • Osteopontin
  • PD-L1

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Osteopontin blockade immunotherapy increases cytotoxic t lymphocyte lytic activity and suppresses colon tumor progression'. Together they form a unique fingerprint.

Cite this