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.
Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer. Although antivascular endothelial growth factor (VEGF) therapies achieve impressive responses in some patients, many tumors eventually develop resistance to such therapy. The B7 family molecules such as CTLA-4, PD-1, and PD-L1 are pivotal players in immune checkpoints that positively or negatively regulate various immune responses. Recently, immunotherapy based on blocking immune checkpoints with anti-CTLA4, anti-PD-1, or anti-PD-L1 antibodies has been proposed as a potential new approach to the treatment of metastatic RCC. Higher expression of PD-L1 and B7-H4 in the tumors is associated with a poor prognosis in RCCs, however, the clinical impact of serum levels of B7 family molecules has not been elucidated in patients with metastatic RCCs receiving VEGF-targeted agents. We assessed the preoperative serum levels of B7 family molecules, including CD80, CD86, PD-1, PD-L1, B7-H3, B7-H4, and CTLA-4, and CD28 in RCC patients, and determined their relations with various clinicopathological characteristics. Elevated preoperative serum levels of PD-L1 and B7-H4 were correlated with less differentiated tumors, higher invasive and metastatic potential, a worse response to anti-VEGF therapy, and shorter overall survival. These findings suggested that investigating preoperative serum levels of PD-L1 and B7-H4 might not only be useful to assess the biological aggressiveness of RCCs, but also to predict the efficacy of anti-VEGF therapy and the eventual prognosis, indicating the future design of clinical trials of therapies targeting immune checkpoint in advanced RCCs.
Department of Urology, Dokkyo Medical University, Tochigi, Japan.
Takehiko
T
Fukuda
Department of Urology, Dokkyo Medical University, Tochigi, Japan.
Takao
T
Kamai
Dialysis center, Dokkyo Medical University Koshigaya Hospital, Saitama, Japan.
Akinori
A
Masuda
Department of Urology, Nasu Red Cross Hospital, Tochigi, Japan.
Akinori
A
Nukui
Department of Urology, Dokkyo Medical University, Tochigi, Japan.
Hideyuki
H
Abe
Department of Urology, Dokkyo Medical University, Tochigi, Japan.
Kyoko
K
Arai
Department of Urology, Dokkyo Medical University, Tochigi, Japan.
Ken-Ichiro
K
Yoshida
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use; D000077784:Axitinib; D060890:B7-H1 Antigen / Q000097:blood*; D014408:Biomarkers, Tumor / Q000097:blood*; D018106:CD28 Antigens / Q000097:blood; D002292:Carcinoma, Renal Cell / Q000175:diagnosis / Q000473:pathology* / Q000556:secondary / Q000628:therapy; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D007093:Imidazoles / Q000627:therapeutic use; D007191:Indazoles / Q000627:therapeutic use; D007211:Indoles / Q000627:therapeutic use; D053208:Kaplan-Meier Estimate; D017567:Karnofsky Performance Status; D007680:Kidney Neoplasms / Q000175:diagnosis / Q000473:pathology* / Q000628:therapy; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009363:Neoplasm Proteins / Q000097:blood; D009392:Nephrectomy / Q000379:methods; D057234:Preoperative Period; D011379:Prognosis; D011758:Pyrroles / Q000627:therapeutic use; D012189:Retrospective Studies; D000077210:Sunitinib; D016896:Treatment Outcome; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000097:blood*; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000097:blood; D055815:Young Adult
D000970:Antineoplastic Agents; D060890:B7-H1 Antigen; D014408:Biomarkers, Tumor; C423236:CD274 protein, human; D018106:CD28 Antigens; D007093:Imidazoles; D007191:Indazoles; D007211:Indoles; D009363:Neoplasm Proteins; D011758:Pyrroles; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1; C467484:VEGFA protein, human; C475826:VTCN1 protein, human; D042461:Vascular Endothelial Growth Factor A; D000077784:Axitinib; D000077210:Sunitinib
Axitinib; B7 family; CD28-family receptors; immune checkpoints; receptor tyrosine kinase inhibitors; renal cell carcinoma; sunitinib