'Myeloid mimicry' identified as driver of immunotherapy resistance in renal medullary carcinoma

Researchers at The University of Texas MD Anderson Cancer Center have found that renal medullary carcinoma (RMC) cells use an adaptive mechanism called "myeloid mimicry" to hide from the immune system and promote disease hyper progression after immunotherapy, highlighting specific targets that overcome treatment resistance in preclinical models.

The study, published today in Nature Communications, was led by Pavlos Msaouel, M.D., Ph.D., Giannicola Genovese, M.D., Ph.D., both associate professors of Genitourinary Medical Oncology, and Jianjun Gao, M.D., Ph.D., professor of Genitourinary Medical Oncology, and Linghua Wang, M.D., Ph.D., associate professor of Genomic Medicine, associate member of the James P. Allison Institute™ and focus area co-lead for the Institute for Data Science in Oncology.

 "We identified a myeloid mimicry pathway that can drive tumor hyper progression following immunotherapy in renal medullary carcinoma. Inhibiting this pathway may offer a promising strategy to advance into clinical studies," Msaouel said.

What is renal medullary carcinoma (RMC) and why is it hard to treat?

RMC is a type of kidney cancer that usually affects young people with sickle cell trait. Previous studies showed that RMC is resistant to immunotherapy and can lead to a poor prognosis. Not only that, but a particular mechanism called myeloid mimicry – a cancer cell's ability to imitate myeloid cells to hide from the immune system – is thought to contribute to immune resistance and disease progression.

To provide more insights into this mechanism, the researchers examined single-cell RNA sequencing data from patients with RMC who were treated with nivolumab and ipilimumab combination immunotherapy.

What does this study mean for patients with treatment-resistant cancers?

The researchers identified specific targets in the myeloid-related pathways of RMC tumor cells that led to immunotherapy resistance and, one in particular – p300 – that when activated, leads to disease hyper progression.

Interestingly, studies have shown that high expression of p300 is associated with a poor prognosis in other solid tumors. The researchers targeted this pathway in preclinical models of RMC using a p300 selective inhibitor developed by MD Anderson's Therapeutics Discovery division. When combined with immunotherapy, this inhibitor prevented hyper progression and improved immune response.

These results suggest that inhibiting this myeloid mimicry mechanism by adding epigenetic modulators to immunotherapy could be an effective approach to improve outcomes for patients with treatment-resistant cancers.