Table 1.

Immunosuppressive drugs taken by solid organ transplants and their effect on immune cells and their non-immunologic effects on tumorigenesis. CsA = cyclosporin A. TAC = tacrolimus. AZA = azathioprine. MMF = mycophenolate mofetil. SIR = sirolimus/rapamycin. EV = everolimus.

Drugs	DCs	Myeloid Cells	NK Cells	Lymphocytes	Non-Immunologic Effects on Tumorigenesis
Calcineurin inhibitors
CsA	Impairs MHC-I antigen processing and presentation [65]	Induction of TGFβ1 production, which suppresses early tumor formation but also stimulates malignant transformation and metastasis of established tumors [66,67,68,69] Induction of granulocytic inflammation and proinflammatory cytokines IL-1β and TNFα [70]	Inhibition of NK cell proliferation; increases the proportion of CD16−CD56brightNK cells, which are not cytotoxic but express IL-10 and IL-13 [71]	Dephosphorylation of NFAT family members NFAT1, NFAT2 and NFAT4, resulting in the inhibition of IL-2 and IL-4 production and the decreased activation and proliferation of T cells [66] Increased Treg/CD8+ T cell ratios; lower IFNy-producing CD4+ T cells numbers [72] Induction of Th22 response [72,73]	Downregulation of NFAT in keratinocytes decreases the expression of tumor suppressor gene P53 [74], the carcinogenic effect of which is potentiated by UV exposure [75]
TAC	Inhibition of CXCL10 and IL-12 production by DC, impairing their T cell priming ability [76] Impairs MHC-I antigen processing and presentation [65]	-	Inhibition of NK cell proliferation; increases the proportion of CD16−CD56brightNK cells, which are not cytotoxic but express IL-10 and IL-13 [71]	Dephosphorylation of NFAT, resulting in the inhibition of IL-2 and IL-4 production, decreased the activation and proliferation of T cells [66]	-
Purine analogues
AZA	-		-	Inhibition of DNA and RNA synthesis, resulting in the suppression of lymphocyte proliferation [71,77] Downregulation of Bcl-xL, resulting in increased apoptosis in CD4+ T cells Inhibition of pro-inflammatory gene expression [77,78]	Increases the photosensitivity of the skin. Promotes the accumulation of 6-thioguanine in the DNA, leading to increased oxidative stress and mutagenesis upon UV irradiation [79]
MMF	-	-	Inhibition of NK cell proliferation; decreases the proportion of CD16−CD56brightNK cells, which are anti-inflammatory [71]. Downregulation of activating NK cell receptors and NK cell cytotoxicity [71]	Inhibition of DNA and RNA synthesis, resulting in the suppression of lymphocyte proliferation [71,77] Downregulation of VCAM-1 expression and the inhibition of recruitment and the migration of lymphocytes [77,80].	-
mTOR inhibitors
SIR	Decreased expression of costimulatory molecules and inflammatory cytokines by moDC Increased expression of NF-kB and other pro-inflammatory cytokines by mDC upon stimulation, and the downregulation of IL-10 and oncogene STAT3 [81]	Prevention of reduced immunosurveillance and constitutive development of cSCC via the downregulation of IL-10 and STAT3 and the upregulation of pro-inflammatory cytokines [81]	-	Binding to FKBP12, which inhibits mTOR signaling, leading to the inhibition of IL-2 signaling and T cell proliferation. Increased differentiation and enhanced CD8+ memory T cell function in the skin, against new antigenic challenges [82]	Anti-proliferative and anti-neoplastic activity [83] Upregulation of cytokine IL-6, resulting in the downregulation of CK10 [84] and less skin tumor formation [85]
EV	-	-	-	Binding to mTOR complex 1, leading to the inhibition of IL-2 signaling and T cell proliferation [4]	Anti-proliferative and anti-neoplastic activity [83] Upregulation of cytokine IL-6, resulting in the downregulation of CK10 [84] and less skin tumor formation [85]