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SPI-CI and SPI-6 cooperate in the protection from effector cell-mediated cytotoxicity

Michael Bots1, Ingrid G M Kolfschoten, Sandra A Bres

  • 1Department of Clinical Oncology, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, 2300 RC, Leiden, The Netherlands.

Blood
|September 30, 2004
PubMed

Insights

Tumors evade immune attack using proteins like SPI-6 and SPI-CI. These serine protease inhibitors prevent cell death and lysis, helping cancer cells survive cytotoxic T lymphocyte responses.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cancer Research

Background:

  • Tumors employ immune evasion strategies, including intracellular anticytotoxic proteins that regulate cell death.
  • The serine protease inhibitor SPI-6 (serine protease inhibitor 6) inhibits granzyme B (GrB) and prevents cytotoxic T lymphocyte (CTL)-mediated apoptosis.
  • SPI-6 alone does not prevent membranolysis, a key mechanism of cytotoxic lymphocyte-induced cell death.

Purpose of the Study:

  • To investigate the mechanisms by which colon carcinoma cells resist membranolysis.
  • To identify novel immune escape molecules involved in tumor cell protection against cytotoxic lymphocytes.

Main Methods:

  • Analysis of colon carcinoma cell lines for resistance to membranolysis.
  • Investigating the role of SPI-6 and a related serpin, SPI-CI (serine protease inhibitor involved in cytotoxicity inhibition), in cellular protection.
  • Biochemical characterization of SPI-CI, including its interaction with granzyme M (GrM) and its protective effects against perforin/GrM-induced lysis.

Main Results:

  • Several colon carcinoma cell lines exhibit resistance to membranolysis.
  • This resistance is dependent on SPI-6 and the co-expression of SPI-CI.
  • SPI-CI, a chymotrypsin-specific inhibitor, irreversibly interacts with Granzyme M and protects cells from perforin/GrM-mediated lysis.
  • SPI-CI expression is found in placenta, testis, early embryogenesis, and cytotoxic lymphocytes, but not in normal colon.

Conclusions:

  • SPI-CI is a novel immune escape molecule that functions alongside SPI-6.
  • Together, SPI-6 and SPI-CI provide comprehensive protection for tumor cells against cytotoxic lymphocyte-mediated killing, encompassing both apoptosis and membranolysis.

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