MTOR at the Transmitting and Receiving Ends in Tumor Immunity.

Yakir Guri,Thierry M Nordmann,Jason Roszik

doi:10.3389/fimmu.2018.00578

Abstract

Cancer is a complex disease and a leading cause of death worldwide. Immunity is critical for cancer control. Cancer cells exhibit high mutational rates and therefore altered self or neo-antigens, eliciting an immune response to promote tumor eradication. Failure to mount a proper immune response leads to cancer progression. mTOR signaling controls cellular metabolism, immune cell differentiation, and effector function. Deregulated mTOR signaling in cancer cells modulates the tumor microenvironment, thereby affecting tumor immunity and possibly promoting carcinogenesis.

Highlights

Tumor bulk is a mass containing heterogeneous cell populations including malignant cancer cells, non-malignant cells, and supporting stroma [1]
Cells expressing high levels of PD-L1 appear to be more sensitive to the Mammalian TORC1 (mTORC1) inhibitor rapamycin, further suggesting that some of the PD-L1 growth-controlling mechanisms are via mTOR signaling
Various mTOR inhibitors are in ongoing clinical trials and the FDA-approved rapalog everolimus is used in various cancer cell types [10]

Summary

INTRODUCTION

Tumor bulk is a mass containing heterogeneous cell populations including malignant cancer cells, non-malignant cells, and supporting stroma [1]. Cells expressing high levels of PD-L1 appear to be more sensitive to the mTORC1 inhibitor rapamycin, further suggesting that some of the PD-L1 growth-controlling mechanisms are via mTOR signaling. These data suggest a functional relationship between mTOR signaling, PD-L1 expression, and resistance to targeted therapies (i.e., TICs). Rapamycin administration leads to reduced TIC levels [61] These data suggest that mTOR activity in a subset of cells within the tumor mass (i.e., intra-tumoral heterogeneity) mediates MDSC accumulation. TGF-β represses mTOR signaling, both in mice and humans, to inhibit NK cell activation [74], suggesting an mTOR-dependent immune suppressive role for TGF-β in tumor microenvironment. Further studies are required to examine how extracellular signals affect mTOR in T cells; the data demonstrate that mTOR signaling differentially regulates T cells

CLINICAL IMPLICATIONS

CONCLUSION