Immunosuppressants/Immunomodulators and Malignancy

Abstract

Individuals with immunosuppressive conditions are at a higher risk of developing malignancies than those in the general population. Immunosuppression weakens tumor immunity, hinders the detection of pro-oncogenic cells, and activates oncogenic viruses. Malignancies arising in immunosuppressed patients tend to be aggressive, have a high incidence of virus-associated cancers, and are reversible in some cases. Notably, immunosuppressive agents influence the frequency and type of malignancies, as well as their clinicopathological features. Organ transplant recipients receive long-term immunosuppressants to prevent acute rejection. Post-transplant malignancies vary depending on the type of drug administered before the onset of these diseases. Patients with rheumatoid arthritis (RA) are treated with long-term immunosuppressive medications, such as methotrexate (MTX). MTX is widely recognized as being associated with a specific type of lymphoproliferative disorder (LPD), known as MTX-associated LPD. Our recent report indicated that the clinicopathological features of rheumatoid arthritis-associated lymphoproliferative disorder (RA-LPD) also vary based on the other anti-RA agents used, such as tacrolimus and tumor necrosis factor inhibitors. Therefore, the clinicopathological characteristics of post-transplant LPD and RA-LPD evolve alongside the changes in the immunosuppressants/immunomodulators administered. Understanding the various characteristics and time trends of immunosuppressive neoplasms, particularly LPDs, in relation to different immunosuppressant/immunomodulator medications is highly valuable in clinical practice.

Keywords: anti-rheumatic agents; immunosuppressive agents; methotrexate; post-transplant lymphoproliferative disorders; post-transplant malignancy; rheumatoid arthritis-associated lymphoproliferative disorders; rheumatoid arthritis-associated malignancy.

Figure 1

Changing patterns of post-transplant malignancy according to immunosuppressive agent [2,14,15,18,36,39,40,45,46,47,50,51,52,53,54,55,56,57,58,59,60,61,62]. The type of cancer depends on the immunosuppressive agents used before the development of the malignancies. As immunosuppressive therapies have advanced, the patterns of malignant tumors in transplant patients have changed, as shown in this figure. Abbreviations: AZ: azathioprine, ca: carcinoma, NHL: non-Hodgkin lymphoma, KS: Kaposi’s sarcoma, SCC: squamous cell carcinoma, MPA: mycophenolate mofetil, MMF: mycophenolate, LPD: lymphoproliferative disorders, CNS: central nervous system, CNI: calcineurin inhibitors, CyA: cyclosporine A, TAC: tacrolimus, MM: malignant melanoma, mTOR: mammalian target of rapamycin, ALG: anti-lymphocyte globulin, ATG: anti-thymocyte globulin.

Figure 2

Changing patterns of rheumatoid arthritis-associated lymphoproliferative disorders according to anti-rheumatic agent [34,191] The clinicopathological features of rheumatoid arthritis-associated lymphoproliferative disorder (RA-LPD) also differ based on the anti-RA agent used, including methotrexate, tacrolimus, and tumor necrosis factor inhibitors, among others, as illustrated in this figure. Abbreviations: MTX: methotrexate, TAC: tacrolimus, LPD: lymphoproliferative disorder, ALCL: anaplastic large cell lymphoma, ABT: abatacept, TCZ: tocilizumab, sIL-2R: soluble interleukin-2 receptor, EBER-1: Epstein–Barr virus-encoded small RNA-1, MALToma: mucosa-associated lymphoid tissue lymphoma, ref.: reference, sTNFi: soluble tumor necrosis factor inhibitor, ETN: etanercept, CRP: C-reactive protein, HL-like lesion: Hodgkin lymphoma-like lesion, TNFi: tumor necrosis factor inhibitor, FL: follicular lymphoma, mTNFi: monoclonal tumor necrosis factor inhibitor, MTX-LPD: methotrexate-associated lymphoid tissue lymphoma, Du: duration.