Combining mTOR Inhibitors and T Cell-Based Immunotherapies in Cancer Treatment

Simple Summary Several clinical protocols are exploring the anticancer effect of immunotherapy combined to targeted therapy. Indeed, emerging evidence demonstrates that small-molecule targeted inhibitors promote the antitumor immune response. In the case of mechanistic target of rapamycin (mTOR) inhibitors, such approach appears initially counterintuitive due to their immunosuppressive properties. Nevertheless, recent studies have highlighted the complex role played by mTOR in immune cell biology and have demonstrated that mTOR inhibitors can promote or repress the immune response in a context-dependent manner. Accordingly, pre-clinical studies have shown that mTOR inhibitors have the potential to increase the antitumor efficacy of immunotherapies. Here, we therefore review the different inhibitors of mTOR and their effects on adaptive immunity related to current immunotherapies. We further discuss the therapeutic opportunities of combining mTOR inhibitors with immunotherapies in cancer treatment. mTOR regulates several processes that control tumor development, including cancer cell growth, angiogenesis and the immune response to tumor. Accordingly, mTOR inhibitors have been thoroughly explored in cancer therapy but have failed to provide long-lasting anticancer benefits. Several resistance mechanisms that counteract the antitumor effect of mTOR inhibitors have been identified and have highlighted the need to use mTOR inhibitors in combination therapies. In this context, emerging evidence has demonstrated that mTOR inhibitors, despite their immunosuppressive properties, provide anticancer benefits to immunotherapies. In fact, mTOR inhibitors also display immunostimulatory effects, in particular by promoting memory CD8(+) T cell generation. Hence, mTOR inhibitors represent a therapeutic opportunity to promote antitumor CD8 responses and to boost the efficacy of different modalities of cancer immunotherapy. In this context, strategies to reduce the immunosuppressive activity of mTOR inhibitors and therefore to shift the immune response toward antitumor immunity will be useful. In this review, we present the different classes of mTOR inhibitors and discuss their effect on immune cells by focusing mainly on CD8(+) T cells. We further provide an overview of the different preclinical studies that investigated the anticancer effects of mTOR inhibitors combined to immunotherapies.

Automated summary

Studies have shown that mTOR inhibitors can promote or inhibit immune responses in certain contexts, helping to enhance the anticancer effects of immunotherapy. Various resistance mechanisms to mTOR inhibitors have been identified, highlighting the potential benefits of combination therapies.