PD-1 therapy might assist by shifting sure immune cells to combat illnesses like kidney most cancers: © inventory.adobe.com.
PD-1 blocking therapy may go partially by altering sure immune cells known as tumor-associated macrophages (TAMs) from serving to the most cancers develop to serving to combat it, in response to Dr. Berkay Simsek, who added that greater ranges of a sort of those cells, known as CD163-positive TAMs, have been linked to raised outcomes with PD-1 remedy in folks with metastatic clear cell kidney most cancers.
Throughout a presentation on the 2025 Kidney Most cancers Analysis Summit, Simsek mentioned efforts to know how CD163-positive TAMs are linked with outcomes to first-line Opdivo (nivolumab) in folks with metastatic clear cell renal cell carcinoma. The analysis additionally checked out whether or not TAMs and exhausted CD8-positive tumor-infiltrating lymphocytes (TILs) are situated close to one another and work together in what’s described as a “spatially outlined area of interest.”
Simsek is a analysis fellow in pathology at Brigham and Girls’s Hospital in Boston, Massachusetts.
Understanding TAMs in Renal Cell Carcinoma and How They Had been Studied
TAMs are identified to suppress the immune system throughout the tumor surroundings. Though they’re usually linked to resistance to immune checkpoint inhibitors in different cancers reminiscent of colorectal and pancreatic cancers, they’ve additionally been related to therapy response in Hodgkin lymphoma. Nevertheless, their position in predicting therapy leads to kidney most cancers stays unclear, Simsek mentioned.
TAMs can result in T-cell exhaustion, in response to research in lab fashions.
“Chemokines launched from activated T cells entice monocytes from the bloodstream into the tumor surroundings. These monocytes then turn out to be macrophages,” Simsek mentioned. “Over time, poor antigen presentation, immunosuppressive interactions between TAMs and TILs, and the discharge of immune-blocking alerts may cause the T cells to turn out to be exhausted and fewer capable of combat the tumor.”
To research, researchers examined tumor samples collected earlier than therapy from 67 sufferers who obtained first-line Opdivo as a part of a part 2 research. The trial additionally assessed the connection between PD-1 expression on regulatory T cells and resistance to Opdivo. Notably, the share of PD-1–constructive regulatory T cells was not considerably linked with how lengthy sufferers remained free from illness development or how nicely they responded to therapy.
“To determine TAMs and CD8-positive TILs in several exhaustion states, we used a technique from our lab involving multiplex immunofluorescent staining,” Simsek defined. CD163-positive TAMs had been recognized, together with non-terminally exhausted CD8-positive TILs (outlined by CD8 and PD-1 expression however unfavourable for TIM3 and LAG3) and terminally exhausted TILs (which expressed CD8, PD-1, and both TIM3 or LAG3).
Within the second a part of the research, statistical and bioinformatics strategies had been used to discover the hyperlink between the variety of CD163-positive TAMs and therapy outcomes. A spatial evaluation was additionally carried out utilizing a software program software to look at how shut TILs had been to TAMs.
Therapy Outcomes Primarily based on CD163-Optimistic TAMs and First-Line Opdivo
The evaluation confirmed that sufferers with extra CD163-positive TAMs had higher response charges and longer time earlier than the illness progressed on Opdivo. In sufferers with excessive ranges of those TAMs (34 sufferers), 65% responded to therapy. Compared, solely 15% of these with low ranges (5 of 33 sufferers) responded.
Median time earlier than illness development was longer for sufferers with excessive ranges of CD163-positive TAMs—16.6 months—in comparison with 5.5 months for these with low ranges.
Spatial Evaluation and the Function of Exhausted CD8-Optimistic TILs
For the spatial evaluation, researchers measured the density of each terminally and non-terminally exhausted CD8-positive TILs inside 30 micrometers of CD163-positive TAMs (outlined as “proximal” areas) and farther away (outlined as “non-proximal” areas).
“We checked out each areas and calculated how concentrated every exhausted TIL group was inside these zones,” Simsek mentioned.
Outcomes confirmed that non-terminally exhausted CD8-positive TILs had been extra concentrated close to TAMs than in areas farther away.
Each forms of exhausted TILs had been discovered close to CD163-positive TAMs, however terminally exhausted CD8-positive TILs had been considerably extra enriched in these areas in comparison with non-terminally exhausted ones.
References
- Simsek S. CD163+ tumor-associated macrophages and scientific outcomes to first-line nivolumab remedy in sufferers with metastatic clear cell renal cell carcinoma: insights from the HCRN GU16-260 trial. Offered at: 2025 Kidney Most cancers Analysis Summit; July 17-18, 2025; Boston, Massachusetts.
- Mohanna R, Simsek B, El Ahmar N, et al. Affiliation between PD-1 expression on tumor-infiltrating regulatory T cells and resistance to first-line nivolumab in superior clear cell renal cell carcinoma: insights from the HCRN GU16-260 scientific trial. J Clin Oncol. 2025;43(suppl 5):590. doi:10.1200/JCO.2025.43.5_suppl.590
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