Cytomegalovirus-Induced γδ T Cells Associate with Reduced Cancer Risk after Kidney Transplantation

Abstract

An increase in the number of blood ␥␦ T cells follows cytomegalovirus (CMV) infection in kidney transplant recipients. These cells react against CMV-infected cells and tumor epithelial cells in vitro. We hypothesized that these CMV-induced ␥␦ T cells play a protective role against cancer in kidney transplant recipients. We performed a longitudinal case-control study involving 18 recipients who developed cancer between 2 and 6 yr after transplantation and 45 recipients who did not. The median percentage of ␥␦ T cells among total lymphocytes in patients with malignancies was significantly lower compared with that in control patients at 6, 12, and 18 mo before the diagnosis of cancer. Patients with a ␥␦ T cell percentage of more than 4% were protected from cancer. An increase of the V␦2 neg ␥␦ T cell subset significantly associated with lower incidence of cancer only in recipients who experienced pre-or postgraft CMV infection. Finally, a retrospective follow-up of 131 recipients for 8 yr revealed that CMV-naive recipients had an approximately 5-fold higher risk of cancer compared with CMV-exposed patients. In summary, these results suggest a protective role of CMV exposure against cancer in kidney transplant recipients.

TCR-dependent sensitization of human γδ T cells to non-myeloid IL-18 in cytomegalovirus and tumor stress surveillance

“…18 Importantly, CMV-induced expansion of Vd2 neg gd T cells correlates with decreased susceptibility to post-transplant cancers, suggesting a role in tumor immunosurveillance in vivo. 19 In line with this, such cells display a TCR-dependent cross-reactivity to several solid tumor cell lines and CMV-infected cells, which can be explained by the recognition of common, specific, stressinduced gd TCR ligands (e.g., EPCR) expressed by cellular targets in both conditions. 18 However, a complex array of co-stimulatory signals along with TCR engagement seem to be required to fine tune appropriate Vd2 neg gd T-cell responses to tissue stress.…”

Identification of human cytomegalovirus in tumour tissues of colorectal cancer and its association with the outcome of non-elderly patients

“…In the elderly, chronic latent HCMV infection increases the mortality rate, which could be attributed to HCMV-induced immunosenescence with decreased immunity to microbes and cancers (Pawelec et al, 2010;Sansoni et al, 2014;Savva et al, 2013). In the non-elderly, on the other hand, chronic HCMV infection may actually be beneficial in that it augments the T-cell immunity and has been associated with a reduced cancer risk in transplant patients (Couzi et al, 2010;Furman et al, 2015;Pera et al, 2014). In this study, significant intra-tumoural inflammatory responses were more frequently observed in HCMVpositive tumours, suggesting that viral replication may activate the immune response in the tumour microenvironment and contribute to a favourable prognosis (Naito et al, 1998).…”

Protection from Cancer in Kidney Transplant Patients by γδ T Cells

“…The report by Couzi et al 1 also raises some interesting questions. Does the increased number of V␦2 Ϫ ␥␦ T cells demonstrate a direct relationship between CMV infection and immune control of certain tumors?…”

“…In this issue of JASN, Couzi et al 1 describe a longitudinal case-control study of kidney transplant recipients who developed cancer 2 to 6 years after transplantation. The median percentage of ␥␦ T cells was significantly lower in patients who developed cancer but only in those who had a pre-or posttransplantation cytomegalovirus (CMV) infection.…”

“…Mice lacking ␥␦ T cells are prone to develop tumors induced by cutaneous carcinogens. 15 The study by Couzi et al 1 provides insights into the potential role of CMV in cancer and highlights differences in immunologic reactivity against tumor cells or the virus that determines the number of circulating ␥␦ T cells in infected individuals. Thus, a reduced number of such cells may identify patients who are at increased risk for developing cancer after transplantation.…”