Costimulatory B7-H1 in renal cell carcinoma patients: Indicator of tumor aggressiveness and potential therapeutic target

Abstract

Expression of B7-H1, a costimulating glycoprotein in the B7 family, is normally restricted to macrophage-lineage cells, providing a potential costimulatory signal source for regulation of T cell activation. In contrast, aberrant expression of B7-H1 by tumor cells has been implicated in impairment of T cell function and survival, resulting in defective host antitumoral immunity. The relationship between tumor-associated B7-H1 and clinical cancer progression is unknown. Herein, we report B7-H1 expression by both renal cell carcinoma (RCC) tumors of the kidney and RCC tumor-infiltrating lymphocytes. In addition, our analysis of 196 clinical specimens reveals that patients harboring high intratumoral expression levels of B7-H1, contributed by tumor cells alone, lymphocytes alone, or tumor and/or lymphocytes combined, exhibit aggressive tumors and are at markedly increased risk of death from RCC. In fact, patients with high tumor and/or lymphocyte B7-H1 levels are 4.5 times more likely to die from their cancer than patients exhibiting low levels of B7-H1 expression (risk ratio 4.53; 95% confidence interval 1.94-10.56; P < 0.001.) Thus, our study suggests a previously undescribed mechanism whereby RCC may impair host immunity to foster tumor progression. B7-H1 may prove useful as a prognostic variable for RCC patients both pre- and posttreatment. In addition, B7-H1 may represent a promising target to facilitate more favorable responses in patients who require immunotherapy for treatment of advanced RCC.

Fig. 1.

Photomicrographs at ×400. (A) RCC specimen with high tumor B7-H1 expression. (B) RCC specimen with high lymphocyte B7-H1 expression. (C) RCC specimen with no B7-H1 staining in either the tumor cells or lymphocytes. (D) Normal kidney specimen with no B7-H1 staining in the proximal tubules.

Fig. 2.

Associations of B7-H1 expression with death from RCC in 196 clear cell RCC specimens. (A) Association of tumor B7-H1 expression with death from RCC (risk ratio 2.91; 95% CI 1.39–6.13; P = 0.005). The cancer-specific survival rates (SE, number still at risk) at 1, 2, and 3 years after nephrectomy were 87.8% (4.1%, 53), 72.3% (6.0%, 30), and 63.2% (7.2%, 11), respectively, for patients with specimens that had ≥10% tumor B7-H1 expression compared with 93.6% (2.3%, 95), 88.4% (3.4%, 48), and 88.4% (3.4%, 19), respectively, for patients with specimens that had <10% tumor B7-H1 expression. (B) Association of adjusted score for lymphocyte B7-H1 expression with death from RCC (risk ratio 3.58; 95% CI 1.74–7.37; P < 0.001). The cancer-specific survival rates (SE, number still at risk) at 1, 2, and 3 years were 83.5% (6.2%, 26), 63.9% (9.2%, 13), and 53.6% (10.2%, 5), respectively, for patients with specimens that had a lymphocyte B7-H1 expression score ≥100 compared with 93.5% (2.1%, 122), 86.2% (3.3%, 65), and 84.8% (3.5%, 25), respectively, for patients with specimens that had scores <100. (C) Association of intratumoral B7-H1 expression with death from RCC (risk ratio 4.53; 95% CI 1.94–10.56; P < 0.001). The cancer-specific survival rates (SE, number still at risk) at 1, 2, and 3 years were 87.0% (3.8%, 61), 70.0% (5.8%, 32), and 61.9% (6.8%, 13), respectively, for patients with specimens that had high-aggregate intratumoral B7-H1 expression compared with 94.9% (2.2%, 87), 91.9% (3.1%, 46), and 91.9% (3.1%, 17), for patients with specimens that had both <10% tumor and <100 lymphocyte (low) B7-H1 expression.