Inhibitors of B7-CD28 costimulation in urologic malignancies

Abstract

T-cell costimulatory molecules deliver positive or negative signals to govern the ultimate fate of immune responses. These ligands and receptors that negatively costimulate T cells (including cytotoxic T-lymphocyte antigen [CTLA]-4, B7-H1, programmed death [PD]-1, B7-H3 and B7x) have received significant interest recently owing to their proposed ability to form a molecular shield for tumor cells. CTLA-4 represents the most extensively studied receptor in the costimulatory pathway and functions as a potent inhibitor of T-cell-mediated immunity. Clinical trials with anti-CTLA-4 are ongoing, although numerous objective responses have been observed in heavily pretreated patients, albeit with autoimmune side effects. In renal cell carcinoma, B7-H1, PD-1 and B7x have been observed to be expressed on tumor cells or infiltrating lymphocytes and are individually associated with adverse pathologic features and poor clinical outcome. In prostate cancer, B7-H3 and B7x immunostaining intensity correlate with disease spread, clinical cancer recurrence and cancer-specific death. External validation and prospective studies are now needed to confirm these findings, while further development of humanized monoclonal antibodies, similar to the experience with anti-CTLA-4, are underway. Herein, we review the B7-CD28 family as it applies to urologic malignancies.

Keywords: lymphocyte activation; prostatic neoplasm; regulatory T lymphocyte; renal cell carcinoma; urinary bladder neoplasm.

Figure 1. T-cell activation requires two independent signals

(A) First, antigen is presented to the TCR via an Ag/MHC. A second antigen-independent signal, termed costimulation, is required to govern the fate of the T cell. When the TCR CD28 interacts with its counter-receptor B7-1 or B7-2, a positive T-cell response is generated. (B) In the presence of CTLA-4, T-cell responses are abrogated and tolerance of presented antigen is allowed. Ag: Antigen; APC: Antigen-presenting cell; CTLA: Cytotoxic T-lymphocyte antigen; TCR: T-cell receptor. Redrawn with permission from [5].

Figure 2. Positive and negative costimulatory signals governing the facte of an activated T-cell

Although required for T-cell activation, the Ag–TCR interaction does not govern the fate of the T cell. Positive costimulatory molecules, such as CD28, 4-1BB, ICOS and OX40 can stimulate a T-cell response specific for the antigen presented. On the other hand, negative costimulatory molecules, such as CTLA-4, can inhibit T-cell activation and may induce anergy (tolerance) to the presented antigen. Ag: Antigen; CTLA: Cytotoxic T-lymphocyte antigen; TCR: T-cell receptor. Redrawn with permission from [5].

Figure 3. CTLA-4 blockade is capable of promoting T cell-mediated regression of solid tumors in mice

Monoclonal antibody blockade of CTLA-4 allows CD28 to interact with its B7-family counter-receptor, thus stimulating a tumor specific T-cell response. Ag: Antigen; APC: Antigen-presenting cell; CTLA: Cytotoxic T-lymphocyte antigen; TCR: T-cell receptor. Redrawn with permission from [5].

Figure 4. Cancer-specific survival in patients with renal cell carcinoma

Association of tumor B7-H1 expression with death from renal cell carcinoma (RCC) for 306 patients with clear-cell RCC (risk ratio: 3.92; 95% CI: 2.61–5.88; p < 0.001). Cancer-specific survival rates at 5 and 10 years following nephrectomy were 42 and 37%, respectively, for patients with positive tumor B7-H1 expression compared with 83 and 77%, respectively, for patients with negative tumor B7-H1 expression. Reprinted with permission from [43].

Figure 5. Metastatic clear-cell renal cell carcinoma specimens express B7-H1 at a rate similar to that of primary specimens

Photomicrograph at ×400. Metastatic renal cell carcinoma specimen to lung with high B7-H1 expression on both tumor cells (white arrow) and infiltrating lymphocytes (black arrow). Reprinted with permission from [41].