Association between PD-1 expression on tumor-infiltrating regulatory T cells and resistance to first-line nivolumab in advanced clear cell renal cell carcinoma: Insights from the HCRN GU16-260 clinical trial.
Abstract
590 Background: Inhibition of PD-1 signaling in regulatory T cells (Tregs) has been shown to enhance their immunosuppressive function. We previously demonstrated that high levels of PD-1 expression on tumor-infiltrating Tregs are associated with resistance to nivolumab (nivo) monotherapy in pretreated patients with advanced clear cell renal cell carcinoma (ccRCC) from the CheckMate-025 trial (Denize et al, 2024). Here, we aim to validate these findings in the first-line setting. Methods: Primary tumor tissues from patients with ccRCC (n=70) treated with first-line nivo in the HCRN GU16-260 clinical trial were analyzed using multiparametric immunofluorescence (IF). The percentage of tumor-infiltrating PD-1+ Tregs was quantified by image analysis. Associations with objective response rate (ORR) and progression-free survival (PFS) were evaluated using logistic and Cox regression models, along with Fisher’s exact test and log-rank test for statistical inference, as appropriate. The alpha level was set at 5% (one-sided). Results: In line with our previous findings, the percentage of PD-1+ Tregs, measured as a continuous variable, did not have a statistically significant association with PFS [HR = 2.62; p = 0.169] or ORR [OR = 0.72; p = 0.42]. Using an optimized cut-off based on the minimal p-value for ORR, patients with a high percentage (≥36%) of PD-1+ Tregs (8/70) experienced shorter median PFS (3.4 vs. 10.9 months; p = 0.001) and a trend toward lower ORR (12.5% vs. 43.6%; p = 0.093) compared to those with a low percentage (62/70). Conclusions: PD-1 expression on tumor-infiltrating Tregs is associated with worse outcomes to first-line nivo therapy in patients with advanced ccRCC, confirming our previous findings. These results highlight the therapeutic potential of targeting Tregs to overcome resistance and improve the efficacy of PD-1 blockade, which is currently being evaluated in a clinical trial (HCRN GU22-587).
Article Details
Journal Info
Journal of Clinical Oncology
Lippincott Williams & Wilkins
Authors (20)
Razan Mohanna
Brigham and Women's Hospital, Boston, MA
Berkay Simsek
Nourhan El Ahmar
Opeyemi Jegede
2Department of Data Science, ECOG-ACRIN Biostatistical Center, Dana-Farber Cancer Institute, Boston, MA
Sayed Matar
Morgan Paul
3Dana-Farber Cancer Institute, Department of Data Science, Boston, United States
Yasmin Nabil Laimon
Brigham and Women's Hospital, Boston, MA
Gabriel Roberti De Oliveira
Andrew Delcea
Brigham and Women's Hospital, Boston, MA
Toni K. Choueiri
Department of Medical Oncology Dana‐Farber Cancer Institute Boston Massachusetts USA
David A. Braun
Naomi Balzer Haas
Abramson Cancer Center at the University of Pennsylvania, Philadelphia, PA
Hans J. Hammers
UT Southwestern Medical Center, Dallas, TX
Mehmet Asim Bilen
From the Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda (A.B.A., N.S., S.N., L.L., L.C.), the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore (J.H.-C.), and the Investigational Drug Branch, Cancer Therapy Evaluation Program, National Cancer Institute, National Institutes of Health, Rockville (H.S., E.S.) — all in Maryland; the Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, MN (K.V.B., M.O., C.M., G.P.B.); AdventHealth Cancer Institute and the University of Central Florida, Orlando (G.S.); Dana–Farber/Harvard Cancer Center, Boston (S.B., B.M.); UNC Lineberger Comprehensive Cancer Center, Chapel Hill (W.Y.K.), and Duke University Medical Center and Duke Cancer Institute, Durham (J.H., S.H.) — both in North Carolina; the University of Kansas Cancer Center, Westwood (R.P.); Memorial Sloan Kettering Cancer Center, New York (M.Y.T., M.J.M., J.E.R.), and Roswell Park Comprehensive Cancer Center, Buffalo (G.C.) — both in...
Mark N. Stein
Columbia University Medical Center, New York, NY
Jeffrey A. Sosman
Northwestern University, Chicago, IL
Catherine J. Wu
David F. McDermott
Division of Medical Oncology, Department of Medicine Beth Israel Deaconess Medical Center Boston Massachusetts USA
Michael B. Atkins
Department of Oncology Georgetown Lombardi Comprehensive Cancer Center Georgetown University Washington District of Columbia USA
Sabina Signoretti