Immune‑transcriptomic correlates of response to alpha‑ versus beta‑emitting PRRT in neuroendocrine tumors

Peptide receptor radionuclide therapy (PRRT) is being used more often to treat certain solid tumors, such as neuroendocrine tumors that express somatostatin receptors and some prostate cancers. One form of PRRT uses a beta‑emitting drug (177Lu‑DOTATATE), which is currently the standard treatment for many of these neuroendocrine tumors. Another, newer approach uses an alpha‑emitting drug (212Pb‑DOTAMTATE), which delivers a different kind of radiation with more intense, localized effects on cancer cells and their environment.

Both types of PRRT kill tumor cells by damaging their DNA, but they also affect the immune system in the body. Researchers wanted to see how treatment with the alpha‑emitter changes the immune system compared with the beta‑emitter, and how these changes relate to whether patients respond to treatment. To do this, they collected whole‑blood samples from patients before and during therapy and used a specialized RNA‑analysis platform to look at changes in immune‑related genes over time.

The study found that the alpha‑emitter therapy caused strong changes in the blood’s immune gene profile in patients who achieved a complete or partial response. These changes started to appear about eight weeks after the first infusion and could still be detected up to six months after the treatment ended. Among responders, the pattern of gene changes was quite similar, suggesting a consistent immune‑activation program. In contrast, the same therapy in non‑responders produced weaker and less consistent immune signals. When compared with patients treated with the beta‑emitter, the alpha‑emitter induced both stronger and different patterns of gene regulation, especially in pathways related to inflammation and cell death.

At the cellular level, the alpha‑emitter triggered early increases in reactive oxygen species, DNA‑damage responses, and signals for apoptosis, along with signs of inflammation and increased recruitment of monocytes—immune cells that help shape broader immune reactions. The data also showed two waves of immune‑related gene changes over time, which may reflect that some patients respond early and others respond later, with different timing in how their immune system is activated.

Both drugs caused lymphopenia, meaning a drop in circulating lymphocytes, with B cells being particularly affected. However, this lymphopenia was generally more pronounced in patients treated with the beta‑emitter. This suggests that while both therapies impair some aspects of the immune system, the beta‑emitter may have a stronger suppressive effect on lymphoid cells, whereas the alpha‑emitter combines DNA‑damage‑driven tumor killing with a more organized, early inflammatory and monocyte‑driven immune response in those who benefit.

Overall, these findings show that changes in the blood’s immune gene profile can reflect how well a patient is responding to radioligand therapy. Whole‑blood RNA analysis acts like a liquid biopsy, capturing how the immune system is being pushed and shaped by each type of radiation. The data support the idea that alpha‑emitting PRRT triggers a more coherent and intense immune‑activation signature in responders, while beta‑emitting PRRT induces broader but less structured changes and more profound lymphocyte loss. This kind of immune‑pharmacodynamic profiling could help identify biomarkers to predict which patients will respond and guide decisions about which type of PRRT to use or whether to combine it with other immune‑targeted treatments.

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