Immunogenomic landscape contributes to hyperprogressive disease after anti-PD-1 immunotherapy for cancer

Although PD-1 blocking immunotherapies demonstrate significant therapeutic promise,a subset of the patients could develop hyperprogressive disease (HPD) withaccelerated tumor growth after anti-PD1 immunotherapy. To elucidate underlyingmechanisms, we compared the mutational and transcriptional landscapes between thepre- and post-therapy tumors of two patients developing HPD after anti-PD-1immunotherapy. In post-therapy HPD tumors, somatic mutations were found in knowncancer genes including tumor suppressor genes such as TSC2 and VHL, along withtranscriptional upregulation of oncogenic pathways including IGF-1, ERK/MAPK,PI3K/AKT, and TGF-β. We found that post-therapy HPD tumors were lessimmunogenic than pre-therapy tumors, concurrent with an increased presence of ILC3cells, a subset of innate lymphoid cells. We also developed a gene expressionsignature predictive of HPD. In summary, we identified the genomics and immunefeatures associated with HPD, which may help identify patients at risk of adverseclinical outcome after anti-PD-1 immunotherapy.