Regulation of Lymphocyte Anti-tumor Response in Metastatic Patients Treated With the mTOR Inhibitor Everolimus

Cancer is the second most-common cause of death in industrialized countries. Preclinical studies and clinical observations have shown the PI3K/AKT/mammalian (mechanistic) target of Rapamycin (known as the 'mTOR-pathway') signaling to be deregulated in several tumors.

The mTOR is evolutionary conserved Serine/Threonine protein kinase that senses and integrates signals from different environmental cues. It is a central regulator of cell growth, cell cycle progression, proliferation and metabolism. It has been found to form two distinct, multiprotein complexes based on the binding with different partners. In a complex with Regulatory-Associated Protein of mTOR (Raptor) mTOR forms mTORC1, whereas when bound to Rapamycin-Insensitive Companion of mTOR (Rictor) than the mTOR Complex 2 (mTORC2) is formed. Not only the structure of both mTOR complexes is different, but also they are characterized by distinct biological functions mediated by individual downstream targets. The mTORC1 promotes cap-dependent translation and elongation, increases Messenger RNA (mRNA) biogenesis as well as promotes ribosome biogenesis - via regulation of p70 ribosomal S6 kinase 1 (p70S6K) as well as the eukaryotic initiation factor 4E (eIF4E) binding protein 1 (4EBP-1). In addition mTORC1 promotes lipid synthesis via sterol regulatory element binding protein 1 (SREBP1) and peroxisome proliferator-activated receptor-γ (PPARγ). The role of the mTORC2 is less defined. The best characterized, mTORC2 target is AKT, which regulates cell survival, metabolism and proliferation as well as differentiation in many primary and cancer cell types. Another direct targets of mTORC2 are the serum- and glucocorticoid-regulated kinase (SGK) controls cell survival and anabolism and protein kinase Cα (PKCα) involved in the control of cytoskeletal organization. Thus constitutive, oncogenic activation of mTOR signaling promotes protein and lipid synthesis needed for the increase in cell mass and it enhances surface transporters expression sustaining better uptake of glucose, amino acids and other nutrients sustaining cell growth and proliferation of transformed cells.

Since mTOR signalling pathway is critical for tumorigenesis, its inhibitors have been strongly wanted. As first approved by FDA in clinical setting was Rapamycin for its activity against transplant organ rejection and as a prophylactic agent in Graft-versus-Host disease after allogenic bone marrow transplantation. The immunosuppressive effects of Rapamycin were initially attributed to its ability to block the Interleukin 2 (IL-2) induced proliferation. However, later this was found not to be the case, and rather work through immunomodulation, in part due to the induction and expansion of T cells with regulatory phenotype. Moreover, in T cells mTORC1 modulates T helper cell differentiation towards Th1 and Th17 fate, while mTORC2 controls Th2 development. Also, Rapamycin is involved in immunostimulation of long-lived memory cluster of differentiation 8+ (CD8+) T cells. In addition to the Rapamycin effect on T cells, the drug exerts an inhibitory effect on the proliferation and function of other immune cells such as dendritic cells, B lymphocytes, Natural Killer cells (NK), neutrophiles and mast cells. Lastly, Rapamycin has been tested as a chemotherapy agent against cancer and it was shown to delay the growth and proliferation and to promote apoptosis of many cancer cell lines, and also to possess anti-angiogenic properties. During the past years different rapalogs have been synthesized among which is Everolimus (RAD001, Afinitor®) that is currently tested in clinical trials phase IV in patients with renal cell carcinoma (RCC) or advance large cell lung cancer with neuroendocrine differentiation as well as in the phase III of metastatic breast cancer. In addition, it is already approved in different tumors when the first-line treatment was ineffective. Even Everolimus seems to be very promising neoplastic agent, there is no clinical data about its effect on the immune competence of the patients. And it still remains unknown whether Everolimus exerts similar to Rapamycin effect on the modulation of the immune system when administrated into cancer patients.