Researchers at the University of Texas MD Anderson Cancer Center have discovered that renal medullary carcinoma (RMC) cells use a process called “myeloid mimicry” to evade the immune system and promote rapid disease progression following immunotherapy treatment. This discovery, published in Nature Communications, came about after a Phase II clinical trial testing a combination therapy of two immune checkpoint inhibitors (ICIs) was halted after all 10 enrolled patients experience rapid disease progression.
“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,” said Pavlos Msaouel, MD, PhD, one of the lead authors of the study published in Nature Communications.
RMC is a rare, aggressive kidney cancer that primarily affects younger people with sickle cell trait. RMC is known to be a resistant immunotherapy, and patients with this form of cancer experience have outcomes with median overall survival of just 13 months and three-year survival of less than five percent.
While previous research has shown that RMC tumors display a “hot” immune-inflamed phenotype—expressing the immune checkpoints CTLA-4 and PD-1—prior clinical trials have shown limited success in ICI monotherapy. Because this would seem contraindicated, researchers have looked for other disease mechanisms such as myeloid mimicry, which enable tumors to evade immune attack and continue progressing.
The Phase II trial at MD Anderson sought to avoid this resistance to a single therapy and instead treat the tumors with a combination of the anti-PD1 drug nivolumab with the anti-CD4 immunotherapy ipilimumab. But after all 10 enrolled patients experienced hyperprogression of RMC, the team halted treatments and began looking for why this occurred.
The researchers had conducted single-cell RNA sequencing before treatment in the trail and then collected and analyzed samples from the same patients after they had experience the rapid progression. The data showed that immune checkpoint therapy (ICT) triggered an interferon-γ response in tumor cells, activating a myeloid mimicry program regulated by the CEBPB/p300 axis, which the team showed was linked to increased tumor cell proliferation and hyperprogression.
“RMC tumor cells undergo distinct transcriptional reconfiguration by engaging interferon gamma receptor 1 (IFNGR1) signaling following combination ICT, leading to the activation of myeloid-affiliated transcriptional circuits mediated by the CEBPB/p300 complex that can promote cell proliferation, resulting in hyperprogression,” the researchers wrote.
Further studies used a genetically engineered mouse model of RMC replicating the hyperprogression seen in patients. The mouse model, designed to mimic the human disease in an immunocompetent setting, confirmed it was myeloid mimicry that was responsible for accelerated tumor growth after ICT. During this research, the MD Anderson team discovered a potential therapeutic target to prevent myeloid mimicry. They showed that knocking out IFNGR1, a receptor involved in interferon signaling, prevented hyperprogression and sensitized tumors to ICT.
However, targeting IFNGR1 directly could potentially cause adverse effects. Instead, the researchers focused on a downstream molecule called p300, a histone acetyltransferase which earlier research has linked with regulating gene expression in this pathway. In addition, other studies have shown that high expression of p300 is associated with poor prognosis in solid tumors, including non-small cell lung cancer, prostate cancer, breast cancer, and others.
The investigators then developed an inhibitor of p300 called IACS-16898, which, when combined with immunotherapy, prevented hyperprogression and improved antitumor immune responses in mouse models.
“These results open therapeutic avenues and prompt the development of future immunotherapy clinical trials combining p300 inhibition with ICT in RMC and potentially other aggressive diseases that may hyperprogress via myeloid mimicry,” the researchers wrote.
