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Antiestrogens affect both pathways of killer cell-mediated oncolysis

S M Haeryfar1, E Nagy, E Baral

  • 1Department of Immunology, Faculty of Medicine, University of Manitoba Winnipeg, Canada.

Anticancer Research
|August 6, 2000
PubMed
Abstract

Insights

Antiestrogenic drugs tamoxifen (TX) and toremifene (TO) enhance cancer cell killing by immune cells. These drugs activate both Fas/FasL and perforin/granzyme pathways, improving cancer immunotherapy outcomes.

Area of Science:

  • Immunology
  • Cancer Biology
  • Pharmacology

Background:

  • Previous studies show antiestrogenic drugs tamoxifen (TX) and toremifene (TO) augment immune cell-mediated cancer cell destruction (oncolysis).
  • The precise mechanisms by which these drugs enhance oncolysis remain incompletely understood.

Purpose of the Study:

  • To elucidate the mechanisms by which antiestrogenic drugs enhance killer cell-mediated cancer cell lysis.
  • To investigate the roles of the Fas/FasL and perforin/granzyme pathways in antiestrogen-augmented oncolysis.

Main Methods:

  • Ovarian carcinoma cells and K562 erythroleukemia cells were used as targets in 51Cr release assays with killer cells and/or anti-Fas antibody CH-11.
  • Calcium (Ca++) chelation was employed to differentiate between Ca++-dependent (perforin/granzyme) and Ca++-independent (Fas/FasL) cytotoxic pathways.
  • Fas expression on target cells was analyzed using flow cytometry.

Main Results:

  • Antiestrogens sensitized ovarian carcinoma cells to lysis by autologous cytotoxic lymphocytes and augmented killing by anti-Fas antibody.
  • TX and TO treatment upregulated Fas expression on some ovarian carcinoma cells but not on Fas-negative K562 cells.
  • Antiestrogen-mediated augmentation of K562 cell lysis was abrogated by Ca++ chelation, indicating involvement of the perforin/granzyme pathway.

Conclusions:

  • Antiestrogenic drugs influence both Fas/FasL and perforin/granzyme pathways in killer cell-mediated cancer cell killing.
  • These findings provide mechanistic insights into how tamoxifen and toremifene can enhance cancer immunotherapy.

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