Identification of a Soluble Form of B7-H1 That Retains Immunosuppressive Activity and Is Associated with Aggressive Renal Cell Carcinoma

Abstract

Purpose Release of inhibitory coregulatory proteins into the circulation may represent one mechanism by which tumors thwart immune responses. Our objective was to determine whether sB7-H1 levels in patients with clear cell renal cell carcinoma (ccRCC) are associated with pathologic features and patient outcome. Experimental Design We developed an ELISA for quantification of sB7-H1 in biologic fluids. Biochemical confirmation of the measured analyte as sB7-H1 was done by protein micro-sequencing using supernates from tumor cell lines. Biological activity of sB7-H1 was assessed in vitro utilizing T cell apoptosis assays. We tested sB7-H1 levels in the sera from 172 ccRCC patients and correlated sB7-H1 levels with pathologic features and patient outcome. Results sB7-H1 was detected in the cell-supernatants of some B7-H1-positive tumor cell lines. Protein sequencing established that the measured sB7-H1 retained its receptor-binding domain and could deliver pro-apoptotic signals to T cells. Higher preoperative sB7-H1 levels were associated with larger tumors (p<0.001), tumors of advanced stage (p=0.017) and grade (p=0.044), and tumors with necrosis (p=0.003). A doubling of sB7-H1 levels was associated with a 41% increased risk of death (p=0.010). Conclusion Our observations suggest that sB7-H1 may be detected in the sera of ccRCC patients and that sB7-H1 may systemically impair host immunity, thereby fostering cancer progression and subsequent poor clinical outcome.

Serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death ligand 1 (sPD-L1) in advanced pancreatic cancer

“…11,23 Serum levels of sPD-1 and sPD-L1 have been reported to be independent prognostic factors in different solid tumors susceptible to immunotherapy targeting the PD-1 axis. 13,14,24 Regulation, provenience and function of the soluble forms of PD-1 and PD-L1 in cancer are still under discussion. 24 This is the first study to examine serum levels of sPD-1 and sPD-L1 in advanced PC.…”

“…[10][11][12] High levels of soluble plasma PD-L1 (sPD-L1) were described as an adverse prognostic factor in several malignancies susceptible to PD-1/PD-L1 blockade, including renal cell cancer and hepatocellular carcinoma (HCC). 13,14 To date, provenience, regulation and immunologic function of sPD-1 and sPD-L1 in cancer remain uncertain. Plasma levels of sPD-1 and sPD- L1 have not yet been determined conjointly in any cancer type.…”

Higher preoperative serum levels of PD‐L1 and B7‐H4 are associated with invasive and metastatic potential and predictable for poor response to VEGF‐targeted therapy and unfavorable prognosis of renal cell carcinoma

“…Frigola et al. reported that an elevated preoperative level of soluble PD‐L1 is associated with an increased risk of death from ccRCC, and they suggested that release of soluble PD‐L1 molecules may be a mechanism by which tumors impair systemic antitumor immunity, suggesting that inactivation or removal of soluble PD‐L1 from the serum could be clinically beneficia 26. Taken together, these findings have focused attention on blockade of PD‐1/PD‐L1 as a possible strategy for antitumor immunotherapy in patients with advanced RCC.…”

“…However, as Frigola et al. suggested, systemic effects either by recirculation of immune cells through PD‐L1, B7‐H4, and VEGF‐positive tumor sites or by the release of biologically active soluble forms of PD‐L1, B7‐H4, and VEGF into the circulation cannot be excluded, indicating that both scenarios can contribute to global immunosuppression 26.…”

Characterization of HPV and host genome interactions in primary head and neck cancers

“…In this case, the virus integrated into an intron flanked by exons 4 and 5, and expression levels of exons 5-7 were attenuated, suggesting that viral integration into this locus resulted in an altered form of PDL1 that is expressed at high levels. Alternative PDL1 transcripts have been reported (37,38) and associated with poor prognosis in renal cell carcinoma (37).…”