CD163+ Tumor-Associated Macrophages Linked to Improved Nivolumab Outcomes in Metastatic Renal Cell Carcinoma
Key Insights
High levels of CD163 (search)-positive tumor-associated macrophages are associated with significantly improved response rates and progression-free survival in metastatic clear cell renal cell carcinoma patients treated with first-line nivolumab.
Patients with high CD163 (search)+ TAM density achieved a 65% response rate compared to 15% in those with low density, with median progression-free survival extending from 5.5 to 16.6 months.
The efficacy of PD-1 (search) blockade may be mediated through reprogramming tumor-associated macrophages from a pro-tumorigenic to anti-tumorigenic state.
New research presented at the 2025 Kidney Cancer Research Summit reveals that high levels of CD163 (search)-positive tumor-associated macrophages (TAMs) are associated with significantly improved clinical outcomes in patients with metastatic clear cell renal cell carcinoma (ccRCC) treated with first-line nivolumab. The findings suggest that the efficacy of PD-1 (search) blockade could be partially mediated by reprogramming TAMs from a pro-tumorigenic to an anti-tumorigenic state.
Berkay Simsek, MD, a research fellow in Pathology at Brigham and Women's Hospital in Boston, Massachusetts, presented data from an analysis of pretreatment tumor samples from 67 patients enrolled in the phase 2 HCRN GU16-260 trial (NCT03117309), which evaluated first-line nivolumab in patients with metastatic ccRCC.
Striking Clinical Outcomes Based on TAM Density
The study revealed dramatic differences in treatment outcomes based on CD163 (search)-positive TAM density. Among patients with high TAM density (n = 34), 65% achieved a response compared with only 15% of patients with low density (n = 5/33; P < .001). The median progression-free survival was 16.6 months (95% CI, 5.5-32.9) versus 5.5 months (95% CI, 4.1-10.6) in patients with high and low density, respectively (P = .009).
The statistical analysis demonstrated robust associations between CD163 (search)-positive TAM density and clinical outcomes. The unadjusted and adjusted odds ratios for objective response rate were 2.21 (95% CI, 1.33-3.69; P = .002) and 2.58 (95% CI, 1.43-4.64; P = .002), respectively, when adjusted for International Metastatic RCC Database Consortium risk group. For progression-free survival, the unadjusted and adjusted hazard ratios were 0.77 (95% CI, 0.61-0.97; P = .029) and 0.78 (95% CI, 0.62-0.98; P = .032), respectively.
Challenging Conventional Understanding of TAMs
The findings challenge conventional understanding of TAMs in cancer immunotherapy. "TAMs promote immune suppression in the tumor microenvironment, despite having a reputation for being associated with resistance to immune checkpoint inhibitors in other cancer types, including colorectal cancer and pancreatic ductal adenocarcinoma," Simsek explained. However, he noted that "the role [of TAMs] as predictors of clinical outcomes still remains somewhat unclear."
The research utilized multiplex immunofluorescent staining to identify CD163 (search)-positive TAMs and CD8 (search)-positive tumor-infiltrating lymphocytes (TILs) in various states of exhaustion. Non-terminally exhausted CD8-positive TILs were defined as cells with co-expression of CD8 and PD-1 (search), but negative for TIM3 (search) and LAG3 (search), while terminally exhausted CD8-positive TILs were defined with co-expression of CD8, PD-1, and either TIM3 or LAG3.
Spatial Interactions Within the Tumor Microenvironment
A key component of the research involved spatial proximity analysis to understand how TAMs and exhausted T cells interact within the tumor microenvironment. The analysis examined cell densities within a 30 μm radius area focused on CD163 (search)-positive TAMs (proximal area) and outside this area (non-proximal area).
The spatial analysis revealed that both terminally and non-terminally exhausted CD8 (search)-positive TIL subsets were enriched in proximity to CD163 (search)-positive TAMs. However, "enrichment levels for terminally exhausted CD8-positive TILs in proximity of the CD163-positive TAMs were significantly higher compared to the enrichment levels of non-terminally exhausted CD8-positive TILs," Simsek concluded.
Mechanistic Insights into TAM Function
The research provides mechanistic insights into how TAMs influence T-cell function in the tumor microenvironment. "Chemokines released from activated T cells cause recruitment of monocytes from blood circulation into [the] TME, and those monocytes develop into differentiated macrophages," Simsek stated. "Later on, ineffective antigen presentation as well as immunosuppressive ligand-receptor interactions between TAMs and TILs, coupled with the secretion of immunosuppressive cytokines into the TME, cause exhaustion of cytotoxic T cells and diminish their ability to mount an effective response against the tumor."
The study also examined PD-1 (search) expression on tumor-infiltrating regulatory T cells (Tregs) and their association with nivolumab resistance. However, the percentage of PD-1-positive Tregs did not show a statistically significant association with progression-free survival (HR, 2.62; P = .169) or objective response rate (OR, 0.72; P = .42).
These findings suggest that CD163 (search)-positive TAMs could serve as a valuable biomarker for predicting nivolumab efficacy in metastatic ccRCC, potentially informing treatment selection and patient stratification strategies.