This study reveals the mechanism by which immune checkpoint inhibitors trigger hyper-progression in renal medullary carcinoma, identifying the IFNγ signaling pathway activates the myeloid transcription program through the CEBPB/p300 axis, providing new intervention targets for drug resistance mechanisms.
Literature Overview
This paper, titled 'Nivolumab combined with ipilimumab induces hyper-progression in renal medullary carcinoma: Results of a phase II trial and preclinical evidence', published in Nature Communications, reviews and summarizes clinical trials and mechanistic studies of immunotherapy for renal medullary carcinoma (RMC). The study found that nivolumab combined with ipilimumab did not produce therapeutic efficacy in RMC patients, but instead led to hyper-progression. Furthermore, scRNA-seq and mouse model analyses revealed the underlying molecular mechanisms.
Background Knowledge
Renal medullary carcinoma (RMC) is a rare but highly aggressive form of kidney cancer, commonly found in young patients with sickle cell trait. Due to its aggressive nature and lack of effective treatment options, patient prognosis is poor. Immune checkpoint therapies (ICT), such as PD-1 and CTLA-4 inhibitors, have been widely used in treating various cancers, but their efficacy in RMC remains unclear. Prior studies suggest that RMC exhibits an immune-inflammatory phenotype, yet clinical responses vary, with some patients experiencing hyper-progression, potentially related to adaptive changes in the tumor microenvironment or specific signaling pathways. This study combines clinical data with mouse models to explore the mechanisms of ICT-induced hyper-progression in RMC, aiming to identify potential intervention targets.
Research Methods and Experiments
The research team conducted a phase II clinical trial (NCT03274258) in RMC patients, with the primary endpoint being objective response rate (ORR), and secondary endpoints including progression-free survival (PFS) and overall survival (OS). The trial was prematurely terminated due to futility, with all ten patients showing rapid disease progression, and five meeting radiological criteria for hyper-progression. Researchers further performed single-cell RNA sequencing (scRNA-seq) on patient samples and found that myeloid markers S100A9 and IFNGR1 were significantly upregulated in RMC cells post ICT treatment, correlating with activation of pathways related to cell cycle and DNA replication. Additionally, by establishing an immune-competent mouse model, the researchers validated that ICT accelerated tumor growth, and found that IFNGR1 knockout or pharmacological inhibition of p300 restored ICT efficacy.
Key Conclusions and Perspectives
Research Significance and Prospects
This study reveals that ICT may activate myeloid reprogramming via the IFNγ-CEBPB/p300 axis in RMC, thereby promoting tumor progression. This mechanism provides new directions for future research on immunotherapy resistance and suggests that targeting p300 or its transcriptional program could be a promising strategy to overcome resistance. Future studies could integrate preclinical models with patient data to identify more precise biomarkers that distinguish patients who may benefit from ICT from those likely to experience hyper-progression, thus optimizing personalized treatment strategies.
Conclusion
This study systematically reveals the phenomenon and mechanism of hyper-progression following immune checkpoint therapy in renal medullary carcinoma, both clinically and experimentally. It was found that ICT induces IFNγ signaling activation, which triggers myeloid transcriptional programs through the CEBPB/p300 axis, thereby enhancing tumor cell plasticity and proliferation. By genetically knocking out IFNGR1 or pharmacologically inhibiting p300, the researchers successfully restored the efficacy of ICT in RMC, offering key therapeutic targets for future treatment strategies. This research not only deepens understanding of the mechanisms of immunotherapy resistance, but also provides potential approaches for precision intervention, showing significant clinical translational potential.
