We read with great interest the review by Monaco (1) on the role of mammalian target of rapamycin inhibitors in the management of posttransplant malignancies, but we would like to provide new insights into alternative antitumor mechanisms of sirolimus (SRL) in posttransplant viral-related tumors. Previous studies attributed the induction of clinical remission of human herpesvirus (HHV)-8–positive posttransplant Kaposi sarcoma (KS), after switch to SRL, to direct antitumor effects of mammalian target of rapamycin inhibition, whereas the absence of response was attributed to acquired drug resistance (1, 2). However, posttransplant-KS may regress after reduction of immunosuppressive therapy, and the role of virus-specific effector T cells in either controlling or preventing the disease has been elucidated (3, 4). Furthermore, we have reported recently that the tumor regression, achieved by switch to SRL in two posttransplant KS liver recipients, nicely correlated with the recovery and the maintenance of both CD8 and CD4 memory responses against the HHV-8 lytic (K8.1) and the latent (orf73) antigens (3). On the contrary, failure to achieve a complete tumor regression in another renal transplant patient treated with SRL was associated with the lack of recovery of HHV-8–specific CD4 memory cells (3). Our findings are also consistent with the recently reported, but yet unexplained, beneficial effect of SRL in the prevention and the treatment of other viral infections, such as hepatitis C virus, cytomegalovirus, and BK virus infections, in transplant recipients (3). Thus, the ability of SRL to allow for the development of protective immune responses against a tumor herpesvirus, in addition to its direct antitumor effect, may play an important role in the regression of posttransplant KS in SRL-treated patients, because posttransplant KS is invariably associated with the absence of peripheral HHV-8–specific T cells against both lytic and latent antigens, at diagnosis (3, 4). Contrary to KS, HHV-8–associated multicentric Castleman disease in HIV-infected subjects has been reported to be associated with the presence of polyfunctional effector memory virus-specific CD8 cells (5). Here, we also extend these findings by showing, for the first time, that in three of four HIV-negative patients, two of whom with primary effusion lymphoma and two with multicentric Castleman disease, the disease onset was associated with the presence of high numbers of circulating virus-specific T cells (Table 1). Altogether, these findings suggest that the pathogenesis of HHV-8–related lymphoproliferative disorders is linked rarely with absent or dysfunctional HHV-8–specific immune responses (5), suggesting that the positive immunomodulatory effects of SRL may not be clinically relevant in this context. Consistent with this, the development of HHV-8–positive primary effusion lymphoma in two transplant patients under treatment with SRL has been reported (1). However, immunologic studies on transplant recipients with HHV-8–positive lymphoproliferations have not yet been performed, to formally address this issue.TABLE 1: HHV-8 viral loads and HHV-8-specific T-cell responses in four HIV negative patients with HHV-8–associated MCD and PEL, at diagnosisOn the basis of available data from the literature, we suggest that virus- specific T-cell response monitoring may be useful and should be implemented in the management of posttransplant KS patients under treatment with SRL, whereas new markers of disease activity are urgently needed to asses the clinical utility of SRL in patients with other HHV-8–related malignancies. Patrizia Barozzi Giovanni Riva Daniela Vallerini Raffaella Bosco Chiara Quadrelli Eleonora Zanetti Leonardo Potenza Fabio Forghieri Giuseppe Torelli Mario Luppi Department of Oncology, Hematology, and Respiratory Diseases University of Modena and Reggio Emilia Modena, Italy