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Clinical Cancer Research 13, 1749-1756, March 15, 2007. doi: 10.1158/1078-0432.CCR-06-2129
© 2007 American Association for Cancer Research
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Imaging, Diagnosis, Prognosis

Survivin and B7-H1 Are Collaborative Predictors of Survival and Represent Potential Therapeutic Targets for Patients with Renal Cell Carcinoma

Amy E. Krambeck1, Haidong Dong2, R. Houston Thompson1, Susan M. Kuntz2, Christine M. Lohse3, Bradley C. Leibovich1, Michael L. Blute1, Thomas J. Sebo4, John C. Cheville4, Alexander S. Parker5 and Eugene D. Kwon1,2

Authors' Affiliations: Departments of 1 Urology, 2 Immunology, 3 Health Sciences Research, and 4 Laboratory Medicine and Pathology, Mayo Medical School, Mayo Clinic, Rochester, Minnesota and 5 Department of Urology, Mayo Clinic, Jacksonville, Florida

Requests for reprints: Eugene D. Kwon, Departments of Urology and Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Phone: 507-284-8371; Fax: 507-284-4987; E-mail: kwon.eugene{at}mayo.edu.


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Purpose: Clear cell renal cell carcinoma (ccRCC) is an immunogenic tumor that can progress in the presence of an intact host immune system. We previously reported that survivin and B7-H1 are independently associated with disease progression and death when expressed by ccRCC tumors. Herein, we examine the clinical effect of ccRCC combined expression of both survivin and B7-H1.

Experimental Design: Specimens from 298 patients who underwent nephrectomy for ccRCC between 1990 and 1994 were immunohistochemically stained for survivin and B7-H1. Cancer-specific survival was estimated using the Kaplan-Meier method. Associations of both markers with ccRCC death were assessed using Cox proportional hazards regression models.

Results: At last follow-up, 94 patients died from ccRCC. Among the living patients, the median follow-up was 11.2 years (range, 0-15 years). There were 177 (59.4%) survivinLow/B7-H1–, 51 (17.1%) survivinHi/B7-H1–, 29 (9.7%) survivinLow/B7-H1+, and 41 (13.8%) survivinHi/B7-H1+ tumors. The 5-year cancer-specific survival rates for patients within each group were 89.3%, 59.7%, 70.0%, and 16.2%, respectively. Combined survivinHi/B7-H1+ expression was associated with ccRCC death univariately (risk ratio, 12.82; 95% confidence interval, 7.50-21.92; P < 0.001) and in multivariate analysis (risk ratio, 2.81; 95% confidence interval, 1.56-5.04; P < 0.001). SurvivinHi/B7-H1+ tumors exhibited increased levels of infiltrating mononuclear cells and survivin-specific T cells compared with survivinLow/B7-H1– tumors.

Conclusion: Patients with survivinHi/B7-H1+ ccRCC tumors are at increased risk of ccRCC death. SurvivinHi/B7-H1+ tumors also harbor increased amounts of infiltrating mononuclear cells and survivin-specific T cells relative to survivinLow/B7-H1– tumors. Taken together, dual expression of survivin and B7-H1 can be used to predict ccRCC tumor aggressiveness.

Both the incidence and mortality associated with clear cell renal cell carcinoma (ccRCC) have increased steadily over the last three decades (1, 2), the latter owing to the increasing numbers of patients who present with metastases either initially or after surgical excision of the primary tumor (2, 3). Conventional chemotherapy and radiation have proven ineffective for advanced ccRCC. However, roughly 20% of advanced ccRCC patients experience a response to systemic cytokine infusion (4–6). Other immunotherapeutic manipulations, such as allogenic stem cell transplant, have proven effective in small cohorts (7, 8). Based on these treatment responses, ccRCC is regarded as an immunogenic malignancy. Functionally impaired mononuclear cells are known to infiltrate ccRCC tumors (9–12), and in clinical studies, such infiltrates are associated with a poor prognosis (13). Thus, there is evidence to support that ccRCC tumors can both activate and disable the host immune system. Despite these observations, few therapeutic advancements have improved upon the 6- to 10-month median survival associated with disseminated ccRCC (14).

Because a large proportion of patients with clinically localized disease will subsequently develop metastases, there is a need to identify biomarkers in primary tumor tissue that not only predict ccRCC aggressiveness but also serve as potential therapeutic targets. Survivin and B7-H1 are two such biomarkers. In an attempt to identify targetable tumor markers, a comparison of gene expression patterns between aggressive and nonaggressive forms of ccRCC was done, revealing that mRNA for the human protein survivin is overexpressed in aggressive ccRCC compared with nonaggressive ccRCC (15). Survivin is a member of the inhibitor of apoptosis protein family that inhibits apoptosis by blocking mitochondrial-dependent caspases (16). Although survivin is undetectable in most adult tissues, it is overexpressed in numerous solid and hematopoietic malignancies (17). Recent evidence suggests that those ccRCC patients who present with tumors that express high levels of survivin are at increased risk of cancer progression and ccRCC death (18).

B7-H1 (also known as PD-L1) is a ligand that inhibits T cell–mediated immunity (19–21). B7-H1, normally expressed on minor subsets of macrophage-lineage cells (19), is also aberrantly expressed on multiple human malignancies (20, 22, 23). In a long-term follow-up study, we recently showed that ccRCC patients harboring tumors expressing B7-H1 are at significantly increased risk for progression and mortality (24, 25).

Both survivin and B7-H1 may promote ccRCC tumor progression: the former by promoting tumor cell immortalization and the latter through evasion of the immune system. Because both of these molecules act via very different mechanisms to preserve tumor cell viability, one might anticipate that ccRCC tumors expressing both of these molecules might behave significantly more aggressively than ccRCC tumors that express either marker alone. Alternatively, one might just as easily predict that these two molecules are randomly produced by increasingly dysplastic cells, overlapping as prognostic variables and acting as surrogate biomarkers for one another. It has not previously been tested whether survivin and B7-H1 represent interchangeable versus additive prognostic markers for assessment of ccRCC, a point that cannot be resolved by inference nor one that has previously been reported in the literature. Hence, we examined the clinical effect of combined survivin and B7-H1 expression in ccRCC tumors obtained from 298 surgically treated patients with more than 10 years of median follow-up. We report that simultaneous survivin and B7-H1 expression within the same ccRCC tumor is associated with decreased cancer-specific survival. Additionally, ccRCC tumors expressing high levels of survivin and B7-H1 (survivinHi/B7-H1+) exhibit increased infiltration by mononuclear cells, including survivin-specific CD8+ T cells, relative to survivinLow/B7-H1– tumors. Thus, survivin and B7-H1 collaborate as predictors of adverse ccRCC behavior and may also work via immunologic mechanisms to worsen ccRCC progression and outcome.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patient selection. Upon approval from the Institutional Review Board, we identified 427 patients treated by nephrectomy for unilateral, sporadic ccRCC between 1990 and 1994 using the Mayo Clinic Nephrectomy Registry. Among these 427 cases, 298 (69.8%) had paraffin-embedded tumor tissues available for study. The cancer-specific survival rates at 5 years for patients with and without tissue available for study were 72.4% and 79.5%, respectively (P = 0.823, log-rank test).

Clinical and pathologic features. The clinical features studied included age, sex, symptoms at presentation, Eastern Cooperative Oncology Group performance status, tumor thrombus level, and type of surgery. Patients with a palpable flank or abdominal mass, discomfort, gross hematuria, acute onset varicocele, or constitutional symptoms, including rash, sweats, weight loss, fatigue, early satiety, and anorexia, were considered symptomatic at presentation.

The pathologic features studied included histologic subtype classified according to the Union Internationale Contre le Cancer and American Joint Committee on Cancer guidelines (26), tumor size, perinephric fat invasion, the 2002 primary tumor classification, regional lymph node involvement, distant metastases, the 2002 tumor-node-metastasis (TNM) stage groupings, nuclear grade, coagulative tumor necrosis, sarcomatoid differentiation, and lymphocytic infiltration (recorded as absent, focal, moderate, or markedly present; ref. 13). The microscopic slides from all specimens were reviewed by a urologic pathologist (J.C.C.) without knowledge of patient outcome or immunostaining results.

Immunohistochemistry for survivin and B7-H1. Two, 5-µm sections from representative paraffin-embedded tissue blocks were sectioned for each member of the cohort. One slide was stained with anti-survivin (DAKO, Carpinteria, CA; 1:100 dilution) using standard techniques (18). The second slide was stained with 5H1, a mouse anti-human monoclonal antibody specific for B7-H1 (25).

Quantification of survivin and B7-H1 protein expression. One pathologist (J.C.C.) reviewed the slides stained with anti-survivin and circled the area of greatest staining for digital image analysis (18). The percentage of total area that stained positive for the anti-survivin antibody was used as an overall measure of survivin expression. Tumors staining for ≥2% survivin are denoted as survivinHi, and those with <2% staining are denoted as survivinLow. The cut point of 2% was determined by Parker et al. using scatter plots of survivin expression against the difference in observed survival and the survival expected from a Cox proportional hazards regression model (18). The percentages of tumor cells that stained positive for B7-H1 were reviewed independently by two urologic pathologists (J.C.C. and T.J.S.) and quantified in 5% increments. The tumor was considered positive for B7-H1 if there was histologic evidence of cell surface membrane staining in at least 5% of the tumor cells. When there was a discrepancy in scoring (most commonly 0% versus 5% staining), the cases were reviewed by both pathologists for a consensus using a double-headed microscope. Tumors positive for B7-H1 are denoted as B7-H1+, and tumors negative for B7-H1 are denoted as B7-H1–.

Immunohistochemical staining and quantification of survivin-specific CD8+ T cells. We randomly selected 10 tumors from the survivinLow/B7-H1– group and 10 from the survivinHi/B7-H1+ group. Slides were deparaffinized in xylene twice for 5 min and rehydrated through a graded series of alcohols. Slides were then washed twice for 5 min each in PBS. For staining, the slides were incubated overnight at 4°C with phycoerythrin-labeled HLA-A*0201/Survivin95-104 pentamer (0.5 µg/mL; ProImmune, Springfield, VA) and FITC-labeled anti-CD8 antibody (0.5 µg/mL; eBiosciences, San Diego, CA), or phycoerythrin-labeled H-2Kd/HA533-541 pentamer that was used as a negative control. After staining, slides were washed thrice for 5 min each in PBS, and coverslips were mounted in Prolong Gold. Using a Leica Confocal Microscope, 10 representative high-power fields (HPF) were evaluated for the number of cells that positively stained for both CD8 and the survivin-specific T-cell receptors.

Statistical methods. Comparisons of survivin and B7-H1 expression by the clinical and pathologic features studied were evaluated using {chi}2 and Fisher's exact tests. Cancer-specific survival and progression-free survival were estimated using the Kaplan-Meier method and compared among groups using log-rank tests. The associations of survivin and B7-H1 expression with outcome were evaluated using Cox proportional hazards regression models univariately, after adjusting for TNM stage, nuclear grade, and Eastern Cooperative Oncology Group performance status and after adjusting for the Mayo Clinic SSIGN (TNM stage, tumor size, nuclear grade, and coagulative tumor necrosis) Score, a composite prognostic score developed specifically for patients with CCRCC (27). These associations were summarized with risk ratios (RR) and 95% confidence intervals (95% CI). Survivin-specific CD8+ T cells were averaged across the 10 HPF for analysis and compared between groups using Wilcoxon rank sum tests. Statistical analyses were done using the SAS software package (SAS Institute, Cary, NC). All Ps were two sided, and P < 0.05 was considered statistically significant.


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Patient follow-up. At last follow-up 171 of the 298 patients studied had died, including 94 patients who died from ccRCC at a median of 2.1 years following nephrectomy (range, 0-13 years). Among the 127 remaining patients, the median duration of follow-up was 11.2 years (range, 0-15 years); 102 (80.3%) of these patients had at least 10 years of follow-up. Cancer-specific survival rates (SE, number still at risk) at 1, 5, and 10 years following nephrectomy were 90.2% (1.8%, 250), 72.4% (2.7%, 180), and 66.7% (2.9%, 120), respectively.

Quantification of survivin and B7-H1 protein expression. Immunohistochemical staining for survivin and B7-H1 is shown in Fig. 1A and B . The mean survivin expression level was 2.3% (median, 1.1%; range, 0.01-35.8%). SurvivinHi expression was noted in 92 (30.9%) tumors. Seventy (23.5%) tumors exhibited aberrant B7-H1 expression. There were 177 (59.4%) survivinLow/B7-H1– tumors, 51 (17.1%) survivinHi/B7-H1– tumors, 29 (9.7%) survivinLow/B7-H1+ tumors, and 41 (13.8%) survivinHi/B7-H1+ tumors. A comparison of clinical and pathologic features by this combination of survivin and B7-H1 expression is shown in Table 1 . The combination of survivin and B7-H1 expression was significantly associated with several adverse clinical and pathologic features, with survivinHi/B7-H1+ tumors often showing the more aggressive phenotype.


Figure 1
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  		Fig. 1. Immunohistochemical staining and tumor immune trap schematic. A, dense tumor cytoplasmic staining for survivin. Photomicrograph, x200. B, positive staining for B7-H1 on tumor cell membranes. Photomicrograph, x200. C, FITC-labeled anti-CD8+ cells (single arrow) and phycoerythrin-labeled MHC survivin-specific pentamer staining (double arrow). Right, combined staining indicating multiple survivin-specific lymphocytes within ccRCC tumor. Photomicrograph, x400. D, illustration of proposed survivin and B7-H1 interaction. 1, survivin is presented on the tumor cell surface as a tumor-specific antigen that is recognized by CTLs. This leads to intense lymphocytic infiltration. 2, CTLs are activated and produce IFN-{gamma}. 3, IFN-{gamma} further stimulates B7-H1 expression by the tumor. 4, B7-H1 induces CTL dysfunction and apoptosis.

 

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  		Table 1. Comparison of clinical features with combination of survivin and B7-H1 expression

 
By univariate analysis, patients with survivinHi tumors were over five times more likely to die from ccRCC compared with patients with survivinLow tumors (RR, 5.14; 95% CI, 3.39-7.79; P < 0.001). The 5-year cancer-specific survival rates for patients with survivinHi and survivinLow tumors were 40.8% and 86.5%, respectively. Patients with B7-H1+ tumors were over four times more likely to die from ccRCC compared with patients with B7-H1– tumors (RR, 4.13; 95% CI, 2.74-6.22; P < 0.001). The 5-year cancer-specific survival rates for patients with B7-H1+ and B7-H1– tumors were 39.1% and 82.5%, respectively. When combined in a model together, survivinHi expression (RR, 4.20; 95% CI, 2.73-6.46; P < 0.001) and B7-H1+ expression (RR, 3.05; 95% CI, 2.00-4.67; P < 0.001) were independently significantly associated with death from ccRCC.

The association of the combination of survivin and B7-H1 expression with cancer-specific survival is illustrated in Fig. 2 . The 5-year cancer-specific survival rates for patients with survivinLow/B7-H1– tumors, survivinHi/B7-H1– tumors, survivinLow/B7-H1+ tumors, and survivinHi/B7-H1+ tumors were 89.3%, 59.7%, 70.0%, and 16.2%, respectively. Cancer-specific survival rates did not differ significantly between patients with survivinHi/B7-H1– tumor expression and those with survivinLow/B7-H1+ tumor expression (P = 0.318, log-rank test). The univariate association of this combination variable with death from ccRCC is summarized in Table 2 . In a multivariate model, the combination of survivinHi/B7-H1+ expression remained significantly associated with death from ccRCC after adjusting for TNM stage, nuclear grade, and Eastern Cooperative Oncology Group performance status (RR, 3.25; 95% CI, 1.77-5.95; P < 0.001) and after adjusting for the SSIGN Score (RR, 2.81; 95% CI, 1.56-5.04; P < 0.001; Table 2).


Figure 2
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  		Fig. 2. Association of the combination of survivin and B7-H1 expression with cancer-specific survival for 298 patients with ccRCC. Cancer-specific survival rates (SE, number still at risk) at 1, 5, and 10 y following nephrectomy were 97.0% (1.3%, 158), 89.3% (2.5%, 132), and 84.2% (3.0%, 93), respectively, for patients with survivinLow/B7-H1–; 86.2% (4.8%, 42), 59.7% (7.2%, 25), and 51.9% (7.6%, 14), respectively, for patients with survivinHi/B7-H1–; 93.0% (4.8%, 26), 70.0% (8.9%, 18), and 57.8% (9.8%, 11), respectively, for patients with survivinLow/B7-H1+; and 63.8% (7.8%, 24), 16.2% (6.3%, 5), and 16.2% (6.3%, 2), respectively, for patients with survivinHi/B7-H1+ tumors.

 

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  		Table 2. Association of the combination of B7-H1 and survivin expression with death from ccRCC for 298 patients with ccRCC

 
To determine the association of combined survivin and B7-H1 expression with cancer progression, we studied the subset of 260 patients with clinically localized (pN0/pNX, pM0) ccRCC, of whom 64 progressed to distant metastases at a median of 1.5 years following nephrectomy (range, 0-12 years). The association of combined survivin and B7-H1 expression with progression-free survival is illustrated in Fig. 3 . The 5-year progression-free survival rates for patients with survivinLow/B7-H1– tumors, survivinHi/B7-H1– tumors, survivinLow/B7-H1+ tumors, and survivinHi/B7-H1+ tumors were 89.8%, 70.3%, 68.2%, and 43.3%, respectively (P < 0.001, log-rank test). Furthermore, in this subset, the combination of survivinHi/B7-H1+ expression was significantly associated with death from ccRCC univariately (RR, 13.59; 95% CI, 5.98-26.44; P < 0.001), after adjusting for TNM stage, nuclear grade, and Eastern Cooperative Oncology Group performance status (RR, 3.32; 95% CI, 1.58-6.98; P = 0.002) and after adjusting for the SSIGN Score (RR, 2.19; 95% CI, 1.00-4.78; P = 0.050; Table 3 ).


Figure 3
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  		Fig. 3. Association of the combination of survivin and B7-H1 expression with progression-free survival for 260 patients with clinically localized ccRCC. Progression-free survival rates (SE, number still at risk) at 1, 5, and 10 y following nephrectomy were 97.4% (1.3%, 148), 89.8% (2.5%, 123), and 84.4% (3.1%, 85), respectively, for patients with survivinLow/B7-H1–; 87.4% (5.3%, 33), 70.3% (7.6%, 21), and 54.3% (9.2%, 9), respectively, for patients with survivinHi/B7-H1–; 80.8% (7.7%, 20), 68.2% (9.3%, 16), and 59.1% (10.1%, 11), respectively, for patients with survivinLow/B7-H1+; and 57.5% (9.8%, 13), 43.3% (10.3%, 5), and 43.3% (10.3%, 2), respectively, for patients with survivinHi/B7-H1+ tumors.

 

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  		Table 3. Association of the combination of B7-H1 and survivin expression with death from ccRCC for 260 patients with clinically localized (pNX/pN0, pM0) ccRCC

 
Lymphocytic infiltration. Focal, moderate, or marked levels of lymphocytic infiltration were noted in 136 (45.6%) of the 298 patients (Table 1). Only 50 (28.3%) of the 177 survivinLow/B7-H1– tumors exhibited lymphocytic infiltration compared with 34 (82.9%) of the 41 survivinHi/B7-H1+ tumors (P < 0.001).

CD8+ T-cell receptor survivin specificity. The average number of CD8+ T cells within survivinLow/B7-H1– tumors was 8.1 per HPF (median, 4.6) compared with 42.7 per HPF (median, 31.2) within survivinHi/B7-H1+ tumors (P = 0.052). The average number of T-cell receptor survivin-specific T cells within survivinLow/B7-H1– tumors was 3.5 per HPF (median, 0.5) compared with 35.1 per HPF (median, 26.6) for survivinHi/B7-H1+ tumors (P = 0.090; Fig. 1C). The average percentage of T-cell receptor survivin-specific T cells for the survivinLow/B7-H1– group was 22.4% (median, 18.4%) compared with 55.4% (median, 79.4%) for the survivinHi/B7-H1+ group (P = 0.064).


   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
Several prognostic scoring systems, principally based on clinical and pathologic features associated with ccRCC, have been developed in an attempt to identify patients at highest risk for cancer progression and death (3, 27–29). However, the identification of tumor-associated molecules capable of serving as therapeutic targets as well as predictors of cancer progression has been less successful. We examined the combined effect of two potentially targetable ccRCC tumor-associated proteins, previously shown to been independently related to ccRCC progression and mortality, on long-term patient outcome.

In this study of patients with more than 10 years of follow-up, we report that combined expression of both survivin and B7-H1 within ccRCC tumors markedly increases the risk for cancer progression and cancer-specific mortality. Patients bearing survivinHi/B7-H1+ tumors experience substantially worse 5-year cancer-specific survival compared with patients harboring tumors expressing either marker alone (survivinHi/B7-H1– tumors and survivinLow/B7-H1+) or not at all (survivinLow/B7-H1–). These associations persist even after adjusting for traditional predictive factors such as tumor stage, grade, and Eastern Cooperative Oncology Group performance status. Moreover, patients with clinically localized (pN0/pNX, pM0) survivinHi/B7-H1+ tumors are considerably more likely to develop metastases compared with tumors expressing either marker alone or not at all. Finally, we show that high-risk survivinHi/B7-H1+ tumors are most likely to harbor intense mononuclear cell infiltrates containing numerous survivin-specific CD8+ T cells.

One mechanism whereby B7-H1 may contribute to ccRCC tumor aggressiveness stems from its established ability to impair T cell–mediated immunity. B7-H1 is a cell surface glycoprotein that is normally expressed on macrophage-lineage cells where it functions as a T-cell costimulatory molecule (19). Aberrant expression of B7-H1 has been shown in more than 20 human malignancies (20, 23, 24). Tumor associated B7-H1 has been shown to induce T-cell apoptosis and impair cytokine production and cytotoxic activity of activated T cells (21). Thus, in the context of tumor progression, B7-H1 has the potential to disable host antitumoral immunity and thereby promote unimpeded malignant progression (20, 30–32). B7-H1 expression is of clinical significance as recent studies show an association between tumor B7-H1 expression in ccRCC with cancer progression and death (24, 25). Moreover, B7-H1 holds promise as a potential therapeutic target. In vivo antibody-mediated blockade has been shown to potentiate CD8+ T-cell antitumoral activity in several murine models (33). We speculate that B7-H1 may be partly responsible for limiting the overall responsiveness of ccRCC to immunotherapeutic treatment by undermining host immunity.

Survivin seems to aid tumor progression and survival by a different mechanism (i.e., inhibition of apoptosis; ref. 16). Survivin is expressed during fetal development but not within adult tissues (34). Aberrant expression of this protein, however, has been reported in most adult human malignancies (35). Survivin is thought to promote tumor progression by rendering cells refractory to programmed death (36). In a clinical setting, we recently reported that survivin is linked with poor cancer-specific survival when expressed at high levels in ccRCC (18). Survivin also promotes and stabilizes mitotic microtubules necessary for cell development and proliferation (37, 38). Given that many current chemotherapeutic treatments are designed to induce tumor cell apoptosis or destabilize mitotic processes, tumor expression of survivin may explain the poor response of ccRCC to conventional chemotherapy regimens.

Our current study implicates survivin and B7-H1 as collaborative biomarkers that work in consort to identify the most aggressive ccRCC tumors. However, a mechanistic understanding of how these proteins confer such a poor prognosis in ccRCC has yet to be determined. One model suggests that the combined effect of survivin and B7-H1 on ccRCC tumor aggressiveness occurs at the cellular level (Fig. 1D). Specifically, it has been shown that tumor cell survivin can be recognized by CTLs (39, 40). In our study, we observed high levels of survivin-specific CD8+ T cells within survivinHi/B7-H1+ tumors relative to the survivinLow/B7-H1– tumors. The CTL recognition of survivin possibly contributes to the significant increase in lymphocytic infiltration that is observed within survivinHi/B7-H1+ tumors. Moreover, activated infiltrating CTLs are capable of producing IFN-{gamma}, which may cause tumor cell B7-H1 expression to be up-regulated as previously described (20). Such increases in tumor cell B7-H1 expression might further inhibit the function of tumor-infiltrating T cells, either through the induction of apoptosis or anergy. In support of this theory, we have observed the presence of IFN-{gamma}–producing lymphocytes only within survivinHi/B7-H1+ tumors and not within survivinLow/B7-H1– tumors (data not shown). Thus, in addition to preventing tumor cell apoptosis, survivin may also lure and activate CTLs within the tumor. The CTLs may then stimulate tumor cells to express B7-H1, thereby facilitating tumor immune evasion.

Alternatively, the combined effect of survivin and B7-H1 to predict aggressive ccRCC behavior may simply represent natural selection. Tumors are essentially the end product of genetic errors. Cellular abnormalities are routinely monitored and destroyed by host immunity, or are self-destroyed through apoptosis. Those tumors capable of evading host surveillance (i.e., expressing B7-H1) or avoiding cell death (i.e., expressing survivin) will be more aggressive and likely to progress. Although this model accounts for the collaborative effect of survivin and B7-H1 to promote aggressive ccRCC tumor behavior, it does not account for the dense mononuclear cell infiltrate nor the preponderance of survivin-specific CD8+ T cells noted in the survivinHi/B7-H1+ tumors.

Admittedly, further studies will be required to confirm our results and establish the exact mechanistic role of survivin and B7-H1 in aggressive ccRCC tumors. Additionally, it is likely that other tumor proteins also work to promote malignant growth and dissemination. Regardless, preclinical investigations suggest that both survivin and B7-H1 represent appealing targets for antitumoral intervention. In vivo antibody-mediated blockade of B7-H1 has been shown to delay tumor growth in murine ccRCC models (20, 30, 33). Preclinical trials with vaccination strategies to generate an antigen-specific immune response against survivin-bearing tumor cells are under way (41). Other studies have looked at the role of dominant-negative survivin mutants in controlling tumor progression (42–45). Such studies hold promise for the development of therapeutic interventions that may prove beneficial for treating those patients at highest risk for cancer progression and mortality.


   Conclusion
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 Abstract
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
Patients presenting with ccRCC tumors that show high levels of both survivin and B7-H1 expression are at increased risk of progression and ccRCC death, even after adjustment for well-known predictors of ccRCC patient outcome. The mechanism whereby these two molecules collaborate to enhance the aggressiveness of ccRCC tumors remains unclear but may involve a coordinated interaction. Given that both survivin and B7-H1 are widely expressed within human malignancies, we anticipate these observations will have broad implications for improving prognostication and treatment of ccRCC and other malignancies.


   Footnotes
 
Grant support: The Richard M. Schulze Family Foundation, Commonwealth Foundation for Cancer Research, and Helen and Martin Kimmel Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: A.S. Parker and E.D. Kwon are co-senior authors.

Conflict of interest: Patent was filed for B7-H1 and survivin as prognostic applications.

Received 8/25/06; revised 12/ 1/06; accepted 12/19/06.


   References
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 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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M. H. Andersen, I. M. Svane, J. C. Becker, and P. t. Straten
The Universal Character of the Tumor-Associated Antigen Survivin
Clin. Cancer Res., October 15, 2007; 13(20): 5991 - 5994.
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