After a century of controversy, the notion that the immune system regulates cancer development is experiencing a new resurgence. An overwhelming amount of data from animal models--together with compelling data from human patients--indicate that a functional cancer immunosurveillance process indeed exists that acts as an extrinsic tumor suppressor. However, it has also become clear that the immune system can facilitate tumor progression, at least in part, by sculpting the immunogenic phenotype of tumors as they develop. The recognition that immunity plays a dual role in the complex interactions between tumors and the host prompted a refinement of the cancer immunosurveillance hypothesis into one termed "cancer immunoediting." In this review, we summarize the history of the cancer immunosurveillance controversy and discuss its resolution and evolution into the three Es of cancer immunoediting--elimination, equilibrium, and escape.

The three Es of cancer immunoediting.

The immunobiology of cancer immunosurveillance and immunoediting

Context Solid organ transplant recipients have elevated cancer risk due to immunosuppression and oncogenic viral infections. Because most prior research has concerned kidney recipients, large studies that include recipients of differing organs can inform cancer etiology. Objective To describe the overall pattern of cancer following solid organ transplantion. Design, Setting, and Participants Cohort study using linked data on solid organ transplant recipients from the US Scientific Registry of Transplant Recipients (1987-2008) and 13 state and regional cancer registries. Main Outcome Measures Standardized incidence ratios (SIRs) and excess absolute risks (EARs) assessing relative and absolute cancer risk in transplant recipients compared with the general population. Results The registry linkages yielded data on 175 732 solid organ transplants (58.4% for kidney, 21.6% for liver, 10.0% for heart, and 4.0% for lung). The overall cancer risk was elevated with 10 656 cases and an incidence of 1375 per 100 000 person-years (SIR, 2.10 [95% CI, 2.06-2.14]; EAR, 719.3 [95% CI, 693.3-745.6] per 100 000 person-years). Risk was increased for 32 different malignancies, some related to known infections (eg, anal cancer, Kaposi sarcoma) and others unrelated (eg, melanoma, thyroid and lip cancers). The most common malignancies with elevated risk were non-Hodgkin lymphoma (n = 1504; incidence: 194.0 per 100 000 person-years; SIR, 7.54 [95% CI, 7.17-7.93]; EAR, 168.3 [95% CI, 158.6-178.4] per 100 000 person-years) and cancers of the lung (n = 1344; incidence: 173.4 per 100 000 person-years; SIR, 1.97 [95% CI, 1.86-2.08]; EAR, 85.3 [95% CI, 76.2-94.8] per 100 000 person-years), liver (n = 930; incidence: 120.0 per 100 000 person-years; SIR, 11.56 [95% CI, 10.83-12.33]; EAR, 109.6 [95% CI, 102.0-117.6] per 100 000 person-years), and kidney (n = 752; incidence: 97.0 per 100 000 person-years; SIR, 4.65 [95% CI, 4.32-4.99]; EAR, 76.1 [95% CI, 69.3-83.3] per 100 000 person-years). Lung cancer risk was most elevated in lung recipients (SIR, 6.13 [95% CI, 5.18-7.21]) but also increased among other recipients (kidney: SIR, 1.46 [95% CI, 1.34-1.59]; liver: SIR, 1.95 [95% CI, 1.74-2.19]; and heart: SIR, 2.67 [95% CI, 2.40-2.95]). Liver cancer risk was elevated only among liver recipients (SIR, 43.83 [95% CI, 40.90-46.91]), who manifested exceptional risk in the first 6 months (SIR, 508.97 [95% CI, 474.16-545.66]) and a 2-fold excess risk for 10 to 15 years thereafter (SIR, 2.22 [95% CI, 1.57-3.04]). Among kidney recipients, kidney cancer risk was elevated (SIR, 6.66 [95% CI, 6.12-7.23]) and bimodal in onset time. Kidney cancer risk also was increased in liver recipients (SIR, 1.80 [95% CI, 1.40-2.29]) and heart recipients (SIR, 2.90 [95% CI, 2.32-3.59]). Conclusion Compared with the general population, recipients of a kidney, liver, heart, or lung transplant have an increased risk for diverse infection-related and unrelated cancers.

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Spectrum of cancer risk among US solid organ transplant recipients.

Cellular transformation and tumor development result from an accumulation of mutational and epigenetic changes that alter normal cell growth and survival pathways. For the last 100 years, there has been a vigorous debate as to whether the unmanipulated immune system can detect and eliminate such altered host derived cells despite the fact that cancer cells frequently express either abnormal proteins or abnormal levels of normal cellular proteins that function as tumor antigens. In this review, we discuss the current state of this argument and point out some of the recent key experiments demonstrating that immunity not only protects the host from cancer development (i.e., provides a cancer immunosurveillance function) but also can promote tumor growth, sometimes by generating more aggressive tumors. The terminology "cancer immunoediting" has been used to describe this dual host protective and tumor promoting action of immunity, and herein we summarize the ever-increasing experimental and clinical data that support the validity of this concept.

Cancer Immunosurveillance and Immunoediting: The Roles of Immunity in Suppressing Tumor Development and Shaping Tumor Immunogenicity

[Hemolytic-uremic syndrome].

Background: Mycophenolic acid kinetics have been reported to vary after renal transplantation, and mycophenolic acid area under the concentration-time curve (AUC) is the best predictor of suppression of graft rejection. Methods: To determine whether mycophenolic acid kinetics vary after renal transplantation and to examine the potential role of enterohepatic recirculation, we investigated the kinetics of mycophenolic acid and mycophenolic acid glucuronide on days 2, 5, and 28 after transplantation in 10 kidney transplant recipients (male/female ratio, 1.5; mean age, 41.7 +/- 5.0 years) given 1 g mycophenolate mofetil twice a day. To facilitate therapeutic drug monitoring, we examined a limited sampling strategy for estimating 12-hour mycophenolic acid [AUC(0-12)]. Results: The mean +/- SE AUC(0-12) for mycophenolic acid on day 28 was 38.5 +/- 1.6 mg . h/L, with a secondary peak 4 to 8 hours after dosing that was attributable to enterohepatic recirculation. Marked variability was shown in the kinetic profile of mycophenolic acid among patients across the three sampling days. Mycophenolic acid AUC(0-12) was positively predicted by both serum creatinine (P = .01) and serum albumin (P = .03) but not by time after transplantation, body weight, or trough concentration. Limited sampling (at 0, 1, 3, and 6 hours) accounted for 84.1% of the variability in the mycophenolic acid AUC(0-12) data and predicted the AUC(0-12) closely (r(2) = 0.954) when evaluated in 10 different kidney transplant recipients. Conclusions: Mycophenolic acid AUC(0-12) is predicted by serum albumin and creatinine after kidney transplantation, and the AUC(0-12) may be determined during the early posttransplant period while the patient remains hospitalized with use of a limited sampling strategy to facilitate therapeutic drug monitoring.

The kinetics of mycophenolic acid and its glucuronide metabolite in adult kidney transplant recipients.

Background. A kidney transplant recipient inadvertently contracted donor-origin melanoma, which was found to be very advanced at presentation. Withdrawal of immunosuppression failed to induce rejection, and interferon-alpha was required. When florid allograft rejection was in progress, the allograft was removed, before it was recognized that the transplanted melanoma was not being simultaneously rejected,

Advanced donor-origin melanoma in a renal transplant recipient: Immunotherapy, cure, and retransplantation

Objectives

 To determine the incidence of transitional cell carcinoma (TCC) in a renal transplant population and to compare the pattern of neoplasia in patients with analgesic nephropathy (AN) with that in other patients.



Patients and methods

Using the Australia and New Zealand Dialysis and Transplant Registry, renal transplant recipients of the Princess Alexandra Hospital with TCC were identified. They were separated into two groups based on their primary disease, i.e. AN (group 1) and other causes of renal failure (group 2). The age at diagnosis of TCC, site, grade, stage of TCC and outcome were then compared between the groups.



Results

There were 250 (15%) patients in group 1 and 1424 (85%) in group 2; seven patients in each group were found to have TCC, which thus occurred more frequently in the AN group (2.8%) than in group 2 (0.49%). In group 1, five patients died, four from metastatic disease; of these, the mean time from transplantation to diagnosis of the initial tumour was 4.4 years, with a mean time from diagnosis to death of 9 months. In contrast, there were no deaths from metastatic disease in group 2. In group 1, all patients had upper tract tumours, with five patients also having bladder involvement. The upper tract tumours tended to be of a high stage and grade (grade II–III) and were aggressive. In group 2, all the tumours were confined to the bladder and tended to be of low stage and grade (grade I–II Ta).



Conclusions

Patients undergoing renal transplantation as a result of AN are at high risk of developing TCCs of the upper urinary tracts. These tumours tend to be of a high grade and stage and the patients have a poor outcome. Screening with urine analysis and voided urine cytology do not appear to be reliable for the early diagnosis of upper renal tract TCCs in the renal transplant patient. We advocate annual cystoscopy and retrograde ureteric catheterization with washings, brushings and radiological imaging to diagnose upper tract TCCs at an early stage. These patients should also be screened before transplantation using the same technique.

Transitional cell carcinoma in renal transplant recipients: the influence of compound analgesics

Expression of the mucosal γ δ T cell receptor V region repertoire in patients with IgA nephropathy. IgA nephropathy (IgAN) is characterized by the deposition of IgA in the glomerular mesangium and often leads to progressive renal dysfunction and kidney failure. We have previously shown that the mesangial IgA is likely to derive from the bone marrow plasma cells, and suggested that a primary abnormality within the mucosal immune system may underly the pathogenesis of IgAN. This study has analyzed the T cell receptor (TCR) variable (V) region expression by γ δ T cells in the intestinal mucosa of patients with IgAN. The Vγ and V δ usage of TCR transcripts was determined using a semiquantitative reverse transcriptase-PCR protocol. Primers specific for the four human Vγ and six V δ subfamilies were used each with a constant (C) γ or C δ specific primer, and the PCR-amplified TCR transcripts were detected by Southern blotting and oligonucleotide hybridization, γ δ TCR V region expression was determined in gut biopsies and peripheral blood of 11 patients with IgAN, and the TCR Vγ and V δ repertoires were compared to those in gut and peripheral blood of 11 control individuals, γ δ T cells in normal blood predominantly expressed Vγ2 (Vγ9 gene) and V δ 2 gene segments whereas those in normal gut mainly expressed Vγ3 and V δ 3. In IgAN patients, V δ 2 was also the predominant V δ gene utilized by peripheral blood γ δ T cells, however, we observed a predominance of Vγ3 and reduced Vγ2 usage by these cells, γ δ T cells in the gut of IgAN patients mainly used Vγ3 and V δ 1. While the γ and δ TCR V region repertoires did not differ significantly between the peripheral blood of patients and controls, there were significant differences in Vγ and V δ repertoire expression between IgAN and control gut biopsies. Vγ3 gene expression was significantly decreased in IgAN gut compared to control gut ( P = 0.023). In addition, there was a significant decrease in V δ 3 gene expression in IgAN gut compared to control gut ( P = 0.043). These findings indicate that a subpopulation of γ δ T cells, which represent the majority of γ δ T cells in normal gut mucosa, are significantly diminished in the gut of patients with IgAN. This suggests that a “hole” in the mucosal γ δ T cell repertoire may play a fundamental role in contributing to the pathogenesis of IgAN.

Expression of the mucosal γδ T cell receptor V region repertoire in patients with IgA nephropathy

Renal cell carcinomas (RCC) contain tumour infiltrating lymphocytes (TIL) but these are essentially immunosuppressed in that they do not generate effective antitumour immune responses in vivo. These TIL comprise predominantly αβ T cells, although γδ T cells are also present. The repertoire of γδ T cells in RCC, however, has not been fully investigated. To identify the γδ T cell populations infiltrating RCC, this study has characterised the γδ T cell receptor (TCR) repertoire expression in these tumours and compared this to autologous normal kidney and autologous peripheral blood. A semi-quantitative reverse transcriptase/polymerase chain reaction technique was used for amplification of rearranged TCR V-C mRNA transcripts. Primers specific for the four human TCR Vγ and six Vδ subfamilies were used, each in conjunction with a primer specific for either the Cγ or Cδ region. The specificity of the PCR products was confirmed by Southern blotting and hybridisation with an internal C region probe. A densitometry score was assigned to each DNA band and the level of V gene expression was determined as a ratio of Cδ gene expression. The γδ TCR expression in each sample was determined as a ratio of Cδ: glyceraldehyde phosphate dehydrogenase densitometry score. This demonstrated that TCR Cδ gene expression was significantly higher in RCC compared to normal kidney (P<0.019), suggesting a selective infiltration of γδ T cells into the tumour. Furthermore, we observed differences in the TCR Vγ and Vδ repertoires between RCC and peripheral blood. Vγ1 expression was significantly decreased (P<0.043) whereas there was an over-representation of Vγ4 transcripts (P<0.028) in RCC compared to blood. A significant reduction in expression of both Vδ1 (P<0.028) and Vδ3 (P<0.051) was also observed within kidney tumour compared to peripheral blood. These findings show that expression of the γδ TCR repertoire in RCC differs from that in peripheral blood and normal kidney.

Michael C. Falk

Papers

The kinetics of mycophenolic acid and its glucuronide metabolite in adult kidney transplant recipients.

Advanced donor-origin melanoma in a renal transplant recipient: Immunotherapy, cure, and retransplantation

Transitional cell carcinoma in renal transplant recipients: the influence of compound analgesics

Expression of the mucosal γδ T cell receptor V region repertoire in patients with IgA nephropathy

Characterisation of γδ T cells in renal cell carcinoma patients by polymerase chain reaction analysis of T cell receptor transcripts