Post-transplant malignancy: Focusing on virus-associated etiologies, pathogenesis, evidence-based management algorithms, present status of adoptive immunotherapy and future directions

Table 6 Immunosuppressive agents, mechanisms of carcinogenesis and cancer risk [9,108,140]

Immuno-suppressive agents	Mechanisms in carcinogenesis	Cancer risk
Polyclonal lymphocyte depleting agents (OKT3/rATG)	Interfere with T-cells, B-cells, NK and DC functions[143-145]	Increased risk of PTLD
Alemtuzumab	Depletes B and T cells	Increased risk[146]
		NHL (2.5-fold rise)
		Colorectal cancer (2.5-fold rise)
		Thyroid cancer (3-fold rise)
		Mixed results with PTLD association[147,148]
Cyclosporine A	Downregulate T-bet dependent immunosurveillance[149]	Suppress immune response against melanomas
	Inhibit antigen presentation by DC[150]	Impairs elimination of oncogenic viruses and overall increased risk of cancer[151]
Tacrolimus	Inhibit antigen presentation by DC[150]	Impairs elimination of oncogenic viruses
		Overall increase risk of PTLD and reduced trough levels substantially decline the risk[152]
Azathioprine	selectively depletion of memory T-cells[153]	Linked to late SCC (of skin) and myelodysplastic syndrome [154]
Mycophenolate (MMF/MPA)	Antiproliferative and antioncogenic potential[155]	Protective and reduce the risk of PTLD
mTOR inhibitors	Promotion of CD8+ central memory T cells[156]	Enhance antiviral immunity
	Upregulate transcription factor T-bet[157]	T-bet regulates cross-talk of innate and adaptive immune cells and has tumour-suppressive activities[158]
	Antioncogenic and antiproliferative role	Overall cancer risk reduction and even regress KS[159]
Belatacept	Inhibitor of T cell proliferation	Unclear though postulated as slight increased risk of oncogenicity[160]

OKT3: Trade name of Monomurab CD3 (a murine monoclonal antibody reacting with CD3 molecule on human T lymphocyte); rATG: Recombinant antithymocyte globulin; NK cells: Natural killer cells, DC: Dendritic cell; PTLD: Post-transplant lymphoproliferative disorders; NHL: Non-Hodgkin’s lymphoma; SCC: Squamous cell carcinomas; KS: Kaposi sarcoma.