Myeloid mimicry mediates hyperprogression in patients with renal medullary carcinoma treated with nivolumab plus ipilimumab

Renal medullary carcinoma (RMC) is a rare but highly aggressive malignancy that mainly afflicts young individuals of African descent and has few treatment options. Despite the approval of combination immune checkpoint therapy (ICT) for other kidney cancers, its efficacy against RMC remains elusive. We conducted a prospective clinical trial of nivolumab plus ipilimumab in patients with RMC. Enrollment was halted for futility after a prespecified interim analysis revealed that all 10 patients experienced rapid disease progression with 5/10 meeting radiological criteria for hyperprogression. Median progression-free survival was only 1.38 months (95% confidence interval (CI): 1.28, 1.60). To elucidate the underlying mechanisms, we analyzed high-quality single-cell RNA sequencing data from RMC patients before and after nivolumab plus ipilimumab treatment. Our analysis suggested that ICT-triggered interferon gamma upregulation induces RMC tumor cells to activate key myeloid regulators such as the CEBPB / p300 complex that promote tumor cell proliferation leading to hyperprogression. Using an immunocompetent somatic mosaic genetically engineered mouse model of RMC, we confirmed that combination ICT induced hyperprogression of primary and metastatic tumors compared with IgG control by hijacking myeloid-affiliated transcriptional circuits. Blocking of this “myeloid mimicry” adaptive mechanism using a selective inhibitor of p300 induced sensitivity to combination ICT in our animal model of RMC. These findings provide novel insights into RMC adaptation to ICT and demonstrate that inhibiting master myeloid regulators can elicit antitumor responses to ICT thus informing the next generation of immunotherapy strategies targeting hyperprogression. We collected samples from a total of 15 patients. 9 patients provided samples for single-cell RNA (scRNA) sequencing, and 6 other patients provided samples for bulk-RNA sequencing. The scRNA samples consisted of fresh tumor biopsy tissues from 7 immunotherapy-naïve patients with Renal Medullary Carcinoma (RMC), and tissues from 2 patients with RMC collected immediately after aggressive progression on nivolumab plus ipilimumab. The bulk-RNA samples included 3 baseline samples and 3 samples from patients with RMC collected after aggressive progression on nivolumab plus ipilimumab treatment. contributor: Moon Shots Cancer Genomics Laboratory (CGL) contributor: MD Anderson institutional Advanced Genomics Technology Core (AGTC) *************************************************************** Raw data is not provided due to patient privacy concerns. ***************************************************************