The effect of Fas/FasL pathway blocking on apoptosis and stemness within breast cancer tumor microenvironment (preclinical study)

Abstract

Evasion of the immune system is the tumor’s key strategy for its maintenance and progression. Thus, targeting the tumor microenvironment (TME) is considered one of the most promising approaches for fighting cancer, where immune cells within the TME play a vital role in immune surveillance and cancer elimination. FasL is one of the most important death ligands expressed by tumor-infiltrating lymphocytes (TILs) and plays a vital role in eliminating Fas-expressing cancer cells via Fas/FasL pathway-induced apoptosis. However, tumor cells can express elevated levels of FasL inducing apoptosis to TILs. Fas/FasL expression is linked to the maintenance of cancer stem cells (CSCs) within the TME, contributing to tumor aggressiveness, metastasis, recurrence, and chemoresistance. This study is considered the first study designed to block the overexpressed FasL on the tumor cells within TME mimicking tissue culture system using rFas molecules and supplementing the Fas enriched tissue culture system with blocked Fas - peripheral blood mononuclear cells PBMCs (using anti-Fas mAb) to protect them from tumor counterattack and augment their ability to induce tumor cell apoptosis and stemness inhibition. A significantly increased level of apoptosis and decreased expression of CD 44 (CSCs marker) was observed within the east tumor tissue culture system enriched with Fas molecules and anti-Fas treated PBMCs and the one enriched with Fas molecules only compared to the breast tumor tissues cultured alone (p < 0.001). Accordingly, we can consider the current study as a promising proposed immunotherapeutic strategy for breast cancer.