Key Immune Cells Linked to Better Kidney Cancer Outcomes

PD-1 blocking treatment may work in part by changing certain immune cells called tumor-associated macrophages (TAMs) from helping the cancer grow to helping fight it, according to Dr. Berkay Simsek, who added that higher levels of a type of these cells, called CD163-positive TAMs, have been linked to better results with PD-1 therapy in people with metastatic clear cell kidney cancer.

During a presentation at the 2025 Kidney Cancer Research Summit, Simsek discussed efforts to understand how CD163-positive TAMs are linked with outcomes to first-line Opdivo (nivolumab) in people with metastatic clear cell renal cell carcinoma. The research also looked at whether TAMs and exhausted CD8-positive tumor-infiltrating lymphocytes (TILs) are located near each other and interact in what is described as a “spatially defined niche.”

Simsek is a research fellow in pathology at Brigham and Women’s Hospital in Boston, Massachusetts.

Understanding TAMs in Renal Cell Carcinoma and How They Were Studied

TAMs are known to suppress the immune system within the tumor environment. Although they are often linked to resistance to immune checkpoint inhibitors in other cancers such as colorectal and pancreatic cancers, they have also been associated with treatment response in Hodgkin lymphoma. However, their role in predicting treatment results in kidney cancer remains unclear, Simsek said.

TAMs can lead to T-cell exhaustion, according to studies in lab models.

“Chemokines released from activated T cells attract monocytes from the bloodstream into the tumor environment. These monocytes then become macrophages,” Simsek said. “Over time, poor antigen presentation, immunosuppressive interactions between TAMs and TILs, and the release of immune-blocking signals can cause the T cells to become exhausted and less able to fight the tumor.”

To investigate, researchers examined tumor samples collected before treatment from 67 patients who received first-line Opdivo as part of a phase 2 study. The trial also assessed the connection between PD-1 expression on regulatory T cells and resistance to Opdivo. Notably, the percentage of PD-1–positive regulatory T cells was not significantly linked with how long patients remained free from disease progression or how well they responded to treatment.

“To identify TAMs and CD8-positive TILs in different exhaustion states, we used a method from our lab involving multiplex immunofluorescent staining,” Simsek explained. CD163-positive TAMs were identified, along with non-terminally exhausted CD8-positive TILs (defined by CD8 and PD-1 expression but negative for TIM3 and LAG3) and terminally exhausted TILs (which expressed CD8, PD-1, and either TIM3 or LAG3).

In the second part of the study, statistical and bioinformatics methods were used to explore the link between the number of CD163-positive TAMs and treatment outcomes. A spatial analysis was also performed using a software tool to examine how close TILs were to TAMs.

Treatment Outcomes Based on CD163-Positive TAMs and First-Line Opdivo

The analysis showed that patients with more CD163-positive TAMs had better response rates and longer time before the disease progressed on Opdivo. In patients with high levels of these TAMs (34 patients), 65% responded to treatment. In comparison, only 15% of those with low levels (5 of 33 patients) responded.

Median time before disease progression was longer for patients with high levels of CD163-positive TAMs—16.6 months—compared to 5.5 months for those with low levels.

Spatial Analysis and the Role of Exhausted CD8-Positive TILs

For the spatial analysis, researchers measured the density of both terminally and non-terminally exhausted CD8-positive TILs within 30 micrometers of CD163-positive TAMs (defined as “proximal” areas) and farther away (defined as “non-proximal” areas).

“We looked at both areas and calculated how concentrated each exhausted TIL group was within those zones,” Simsek said.

Results showed that non-terminally exhausted CD8-positive TILs were more concentrated near TAMs than in areas farther away.

Both types of exhausted TILs were found near CD163-positive TAMs, but terminally exhausted CD8-positive TILs were significantly more enriched in those areas compared to non-terminally exhausted ones.

References

1. Simsek S. CD163+ tumor-associated macrophages and clinical outcomes to first-line nivolumab therapy in patients with metastatic clear cell renal cell carcinoma: insights from the HCRN GU16-260 trial. Presented at: 2025 Kidney Cancer Research Summit; July 17-18, 2025; Boston, Massachusetts.
2. Mohanna R, Simsek B, El Ahmar N, et al. 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. J Clin Oncol. 2025;43(suppl 5):590. doi:10.1200/JCO.2025.43.5_suppl.590

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