Dissecting the Tumor Microenvironment to Identify Biomarkers of Outcome to Anti-PD-1 Therapy in Clear-Cell Renal Cell Carcinoma: Analyses of the HCRN GU16-260 Trial.

PURPOSE: We investigated components of the immune tumor microenvironment as determinants of clinical outcome to anti-PD-1 therapy in patients with metastatic clear-cell renal cell carcinoma (ccRCC) treated with first-line nivolumab in the phase II, nonrandomized HCRN GU16-260 trial.

EXPERIMENTAL

DESIGN

Pretreatment primary ccRCCs from 72 patients were analyzed via multiplex immunofluorescence and image analysis to assess nonterminally exhausted CD8+ (CD8+PD-1+TIM-3-LAG-3-) tumor-infiltrating lymphocytes (TIL), PD-1+ regulatory T cells (Treg), total and peritumoral tertiary lymphoid structures (TLS), and CD163+ tumor-associated macrophages (TAM). Clinical endpoints included objective response rate (ORR) and progression-free survival (PFS).

RESULTS

The densities of CD8+PD-1+TIM-3-LAG-3- TILs, total and peritumoral TLSs, and CD163+ TAMs, as continuous variables, were associated with improved ORR [odds ratio: 1.54 (1.10-2.16) for TILs; 1.18 (1.02-1.37) for total TLSs; 1.10 (1.02-1.18) for peritumoral TLSs; and 2.21 (1.33-3.69) for TAMs] and longer PFS [hazard ratio: 0.79 (0.67-0.95) for TILs; 0.92 (0.85-0.99) for total TLSs; 0.94 (0.90-0.98) for peritumoral TLSs; and 0.77 (0.61-0.97) for TAMs]. Although the percentage of PD-1+ Tregs as a continuous variable was not associated with outcomes, at an optimal cutoff, a high percentage of PD-1+ Tregs tended to be associated with lower ORR (12.5% vs. 43.6%, P = 0.093) and was associated with shorter PFS (3.4 vs. 10.9 months, P < 0.001). The biomarkers were not strongly correlated with each other, and their integration in multibiomarker models further stratified outcomes.

CONCLUSIONS

Individual immune cell populations within the ccRCC microenvironment are associated with response/resistance to first-line anti-PD-1 therapy. Our findings support the development of combined immune marker models to identify patients with divergent outcomes.