Everolimus combined with PD-1 blockade inhibits progression of triple-negative breast cancer

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer. Due to rapid progression and a lack of targetable receptors, TNBC is exceptionally difficult to treat. Available treatment options are nonspecific cytotoxic agents, which have had modest success; thus, there is a need for novel therapies for TNBC. The mammalian/mechanistic target of rapamycin (mTOR) signaling pathway is aberrantly activated in TNBC, and this pathway has been shown to promote cancer cell survival and chemoresistance. As such, mTOR inhibition has been considered a potential therapeutic strategy for TNBC. The mTOR inhibitor everolimus (EVE) has been approved for the treatment of estrogen positive breast cancer; however, its efficacy in TNBC is still undetermined. In this study, we evaluated the effects of EVE monotherapy and the mechanism of EVE resistance in the 4T1 model of TNBC. Whereas EVE monotherapy inhibited mTOR signaling activity, it did not attenuate tumor progression. Additionally, tumors from EVE-treated mice had abnormal vasculature characterized by disorganized architecture and hyperpermeability. We also found that treatment with EVE increased PD-L1 expression in intratumoral vascular endothelial cells, and this increase in endothelial cell-associated PD-L1 corresponded to reduced CD8 + T cell tumor infiltration. Importantly, combination treatment with anti-PD-1 antibody and EVE normalized the tumor vasculature, rescued CD8 + T cell tumor infiltration, and reduced tumor growth. Taken together, our findings improve our current understanding of mechanisms underlying mTOR inhibition resistance in TNBC and identify a novel combination treatment strategy in the treatment of mTOR resistant tumors.

Automated summary

Triple-negative breast cancer (TNBC) is a challenging subtype to treat due to lack of targetable receptors. The mTOR signaling pathway has been implicated in TNBC and mTOR inhibition is considered a potential therapeutic strategy. However, the efficacy of mTOR inhibitor everolimus (EVE) in TNBC is still unclear. In this study, we found that EVE monotherapy inhibited mTOR signaling but did not slow tumor progression. Additionally, EVE treatment led to abnormal tumor vasculature and increased PD-L1 expression, resulting in reduced CD8+ T cell infiltration. Combination treatment with anti-PD-1 antibody and EVE normalized tumor vasculature, restored CD8+ T cell infiltration, and reduced tumor growth. Our findings provide insights into mTOR inhibition resistance and propose a novel combination treatment strategy for mTOR resistant TNBC tumors.