Clinically-Relevant Rapamycin Treatment Regimens Enhance CD8⁺Effector Memory T Cell Function In The Skin and Allow their Infiltration into Cutaneous Squamous Cell Carcinoma

Abstract

Patients receiving immunosuppressive drugs to prevent organ transplant rejection exhibit a greatly increased risk of developing cutaneous squamous cell carcinoma (SCC). However, not all immunosuppressive drugs confer the same risk. Randomised, controlled trials demonstrate that switching renal transplant recipients receiving calcineurin inhibitor-based therapies to mammalian target of rapamycin (mTOR) inhibitors results in a reduced incidence of SSC formation, and can even result in the regression of pre-existing premalignant lesions. However, the contribution played by residual immune function in this setting is unclear. We examined the hypotheses that mTOR inhibitors promote the enhanced differentiation and function of CD8 memory T cells in the skin. Here, we demonstrate that the long-term oral administration of rapamycin to achieve clinically-relevant whole blood drug target thresholds, creates a "low rapamycin dose" environment in the skin. While both rapamycin and the calcineurin inhibitor tacrolimus elongated the survival of OVA-expressing skin grafts, and inhibited short-term antigen-specific CD8 T cell responses, rapamycin but not tacrolimus permitted the statistically significant infiltration of CD8 effector memory T cells into UV-induced SCC lesions. Furthermore, rapamycin uniquely enhanced the number and function of CD8 effector and central memory T cells in a model of long-term contact hypersensitivity provided that rapamycin was present during the antigen sensitization phase. Thus, our findings suggest that patients switched to mTOR inhibitor regimens likely experience enhanced CD8 memory T cell function to new antigen-challenges in their skin, which could contribute to their lower risk of SSC formation and regression of pre-existing premalignant lesions.

Dissecting the Multiplicity of Immune Effects of Immunosuppressive Drugs to Better Predict the Risk of de novo Malignancies in Solid Organ Transplant Patients

“…In fact, RAPA was shown to promote the generation of long-lived memory precursors by altering the process of differentiation of short-lived precursors (87, 88). These findings are consistent with the possibility that the lower risk of de novo SCC showed by patients switched to mTORi regimens is probably due to enhanced CD8 + memory T-cell responses to new antigenic stimulations occurring in their skin (89).…”

Healing of sub-critical femoral osteotomies in mice is unaffected by tacrolimus and deletion of recombination activating gene 1

“…All mice were housed under specific pathogen-free conditions at the Biological Research Facility, Translational Research Institute, Brisbane, Australia. Jung et al (2018) confirmed that mice in this facility are fully immune-competent (unless genetically immunocompromised).…”

“…Tacrolimus enhances osteogenesis by binding to FK-binding protein 12 within cells, which stimulates intra-cellular signalling through the Smad pathway (Kugimiya et al, 2005).…”

Rapamycin enhances BCG-specific γδ T cells during intravesical BCG therapy for non-muscle invasive bladder cancer: a randomized, double-blind study

“…Lack of efficacy of BCG is likely multifactorial, but may be related to age-dependent decline in immune function. As mTOR inhibition improves antigen-specific immunity, 8 9 rapamycin could facilitate CD4 + and CD8 + T cell responses critical for BCG efficacy, 10 resulting in improved BCG efficacy in elderly persons, 11 an important consideration for bladder cancer patients who have a median age of 70 at diagnosis. 12 mTOR inhibition can also improve T cell memory.…”