Targeting p300 may boost immunotherapy in kidney cancer

Researchers at The University of Texas MD Anderson Cancer Center have discovered that renal medullary carcinoma (RMC) cells use an adaptive mechanism known as ‘myeloid mimicry’ to evade the immune system, promoting rapid disease progression after immunotherapy. The study highlights potential targets that could overcome treatment resistance in preclinical models.

“We identified a myeloid mimicry pathway that can drive tumour hyper progression following immunotherapy in renal medullary carcinoma. Inhibiting this pathway may offer a promising strategy to advance into clinical studies,” said research leader Dr Pavlos Msaouel.

Understanding RMC and its treatment challenges

Renal medullary carcinoma is a rare form of kidney cancer that typically affects young people with sickle cell disease. Previous research has shown that RMC is largely resistant to immunotherapy, meaning patients often face poor outcomes.

Renal medullary carcinoma is a rare form of kidney cancer that typically affects young people with sickle cell disease.

One key factor in this resistance is myeloid mimicry – a process by which cancer cells imitate myeloid cells, effectively hiding from the immune system and allowing the tumour to progress unchecked.

To explore this mechanism further, the researchers analysed single-cell RNA sequencing data from RMC patients who had been treated with a combination of the immunotherapy drugs nivolumab and ipilimumab.

Targeting myeloid mimicry in preclinical models

The study identified specific myeloid-related pathways in RMC tumour cells that contribute to immunotherapy resistance. One protein, p300, was found to drive hyper progression when activated. High expression of p300 has also been linked to poor prognosis in other solid tumours.

Using preclinical models of RMC, the team tested a p300-selective inhibitor developed by MD Anderson’s Therapeutics Discovery division. When administered alongside immunotherapy, the inhibitor prevented hyper progression and improved the immune response against tumours.

Implications for treatment-resistant cancers

These findings suggest that targeting the myeloid mimicry mechanism with epigenetic modulators could enhance the effectiveness of immunotherapy in patients with treatment-resistant cancers like RMC.

The study represents a significant step forward in understanding how certain cancers evade the immune system.

By pinpointing these pathways, the research opens new possibilities for clinical trials aimed at improving outcomes for patients that have historically faced limited treatment options.

The study represents a significant step forward in understanding how certain cancers evade the immune system and highlights the potential of combining targeted therapies with existing immunotherapies to overcome resistance.