Rapamycin is a natural compound and small molecule named after Rapa Nui, the native name for Easter Island. Rapamycin provided the stimulus for research studies on the mammalian target of rapamycin (mTOR) pathway that controls a range of biological processes. In cancer, this protein (mTOR) is frequently activated, leading to uncontrolled cell growth. Rapamycin inhibits mTOR thus it can reduce cell proliferation in cancer cells. However, due to the complexity of the mTOR signaling network, it can lead to different responses in different cell types.
When a disease and its associated antigens persist at high levels, like in cancer, T- cells can suffer from T cell exhaustion, which is regulated by mTOR. Exhausted T cells (Tex) have a sustained expression of inhibitory receptors. T-cell exhaustion is a complicated process involving many factors including altered cell function, upregulation of receptors, changes in transcription factors, metabolic changes, and loss of the ability to enter a quiescent state to form memory T cells, along with many others that have yet to be identified.
T-cell exhaustion is also a concern for Chimeric antigen receptor (CAR) T cell therapies. In this state, the cells lose their ability to target and kill cancer cells, effectively acquiring a state of hypo-responsiveness, which limits their effector function. In this capacity, Rapamycin has been shown to decrease the expression of exhaustion markers, and upregulate genes related to cell memory and survival.
Due to its role in cancer, mTOR has become a target and mTOR inhibitors like Rapamycin are being reviewed as potential anti-cancer agents.
Future discoveries may shed more light on mTOR signaling, mTOR inhibitors, and the role of Rapamycin for cancer research and CAR-T cell technologies.
References
Bulliard Y et al (2023) Reprogramming T cell differentiation and exhaustion in CAR-T cell therapy. J Hematol Oncol 16:108 Link
Chen Y et al (2023) Regulation of CD8+ T memory and exhaustion by the mTOR signals. Cell Mol Immunol 20: 1023–1039 (2023) Link
Yin X, He L, Guo Z (2023) T-cell exhaustion in CAR-T-cell therapy and strategies to overcome it. Immunology. 169(4):400-411. doi: 10.1111/imm.13642. Epub 2023 Mar 20. PMID: 36942414. Link.