mTOR co-targeting strategies for head and neck cancer therapy

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide. There is an urgent need to develop effective therapeutic approaches to prevent and treat HNSCC. Recent deep sequencing of the HNSCC genomic landscape revealed a multiplicity and diversity of genetic alterations in this malignancy. Although a large variety of specific molecules were found altered in each individual tumor, they all participate in only a handful of driver signaling pathways. Among them, the PI3K/mTOR pathway is the most frequently activated, which plays a central role in cancer initiation and progression. In turn, targeting of mTOR may represent a precision therapeutic approach for HNSCC. Indeed, mTOR inhibition exerts potent anti-tumor activity in HNSCC experimental systems, and mTOR targeting clinical trials show encouraging results. However, advanced HNSCC patients may exhibit unpredictable drug resistance, and the analysis of its molecular basis suggests that co-targeting strategies may provide a more effective option. In addition, although counterintuitive, emerging evidence suggests that mTOR inhibition may enhance the anti-tumor immune response. These new findings raise the possibility that the combination of mTOR inhibitors and immune oncology agents may provide novel precision therapeutic options for HNSCC.

Keywords: Head and neck cancer; Immune oncology; Precision therapy; mTOR.

Fig. 1

Frequent genetic alterations of PI3K/mTOR signaling pathway in HNSCC. Data was extracted from the HNSCC Cancer Genome Anatomy (TCGA) effort, including 428 HPV(−) and 76 HPV(+) HNSCC samples. Alterations identified in each key gene are shown, percentages outside and inside parentheses represent HPV(−) and HPV(+) samples, respectively. Red represents oncogene mutations and amplifications, and green represents tumor suppressor gene mutations and copy losses (copy loss refers to homozygous and heterozygous deletion of genes)

Fig. 2

mTOR inhibition may enhance the anti-tumor immune response. A DCs capture tumor antigens and present them to T cells through MHC (class I and class II) pathways. mTOR inhibition induces apoptotic cells, which may contribute as vaccination in situ. B mTOR inhibition drives T cells toward long-lived tumor specific memory T cells. C The inhibitory molecule PDL1 from tumor cells can bind PD1 in T cells and weaken effector T cell’s function. Co-targeting mTOR may reduce PD-L1 expression, restraining PD-L1/PD1 mediated inhibition. Effector T cells refer to as cytotoxic T cells (CD8+) and helper T cells (CD4+). D Immunosuppressive cytokines secreted by Tregs and MDSCs inhibit anti-tumor response. mTOR inhibition may prevent cytokine secretion by regulation of their translational control. DCs dendritic cells, MHC major histocompatibility complex, Tregs regulatory T cell, MDSCs myeloid-derived suppressor cells