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PD-1 Is Expressed by Tumor-Infiltrating Immune Cells and Is Associated with Poor Outcome for Patients with Renal Cell Carcinoma

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

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.

Purpose: B7-H1 is expressed by clinically aggressive forms of renal cell carcinoma (RCC) and predicts adverse outcome. B7-H1 is known to impair host immunity via interaction with the Programmed Death-1 (PD-1) receptor, which is expressed by activated T cells. Levels of immune cells expressing PD-1 (PD-1⁺) in clinical RCC tumors have not been evaluated. Thus, we tested whether immune cell PD-1 expression is observed within aggressive RCC tumors.

Experimental Design: Between 2000 and 2003, 267 patients underwent nephrectomy at our institution for clear cell RCC and had fresh-frozen tissue available for review. These RCC specimens were immunostained using anti–PD-1 (clone MIH4) and outcome analyses were conducted.

Results: Mononuclear immune cell infiltration was observed in 136 (50.9%) specimens. PD-1⁺ immune cells were present in 77 of these 136 (56.6%) tumors. In contrast, RCC tumor cells did not express PD-1. Patients with PD-1⁺ immune cells were significantly more likely to harbor B7-H1⁺ tumor cells (P < 0.001), larger tumors (P = 0.001), and tumors of higher nuclear grade (P = 0.001). Likewise, intratumoral PD-1⁺ immune cells were associated with advanced tumor-node-metastasis stage (P = 0.005), coagulative tumor necrosis (P = 0.027), and sarcomatoid differentiation (P = 0.008). With a median follow-up of 2.9 years, 52 patients died from RCC. Univariately, patients with PD-1⁺ immune cells were at significant risk of cancer-specific death compared with PD-1^– patients (risk ratio, 2.24; P = 0.004).

Conclusions: Levels of immune cells expressing PD-1 were increased in patients with high-risk RCC tumors. Interactions between immune cell PD-1 and B7-H1 may promote cancer progression by contributing to immune dysfunction in patients with RCC.

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