Patients with prostate cancer (PC) generally do not respond favorably to immune checkpoint inhibitors, which may be due to a low abundance of tumor-infiltrating lymphocytes even when mutational load is high. Here, we identified a patient who presented with high-grade primary prostate cancer with two adjacent tumor nodules. While both nodules were mismatch repair-deficient (MMRd), exhibited pathogenic MSH2 and MSH6 alterations, had a high tumor mutational burden (TMB), and demonstrated high microsatellite instability (MSI), they had markedly distinct immune phenotypes. The first displayed a dense infiltrate of lymphocytes ("hot nodule"), while the second displayed significantly fewer infiltrating lymphocytes ("cold nodule"). Whole-exome DNA analysis found that both nodules shared many identical mutations, indicating that they were derived from a single clone. However, the cold nodule appeared to be sub-clonal relative to the hot nodule, suggesting divergent evolution of the cold nodule from the hot nodule. Whole-transcriptome RNA analysis found that the cold nodule demonstrated lower expression of genes related to antigen presentation (HLA) and, paradoxically, classical tumor immune tolerance markers such as PD-L1 (CD274) and CTLA-4. Immune cell deconvolution suggested that the hot nodule was enriched not only in CD8+ and CD4 + T lymphocytes, but also in M1 macrophages, activated NK cells, and γδ T cells compared to the cold nodule. This case highlights that MMRd/TMB-high PC can evolve to minimize an anti-tumor immune response, and nominates downregulation of antigen presentation machinery (HLA loss) as a potential mechanism of adaptive immune evasion in PC.
NPJ genomic medicine. 2024 Jan 22*** epublish ***
Hannah E Bergom, Laura A Sena, Abderrahman Day, Benjamin Miller, Carly D Miller, John R Lozada, Nicholas Zorko, Jinhua Wang, Eugene Shenderov, Francisco Pereira Lobo, Fernanda Caramella-Pereira, Luigi Marchionni, Charles G Drake, Tamara Lotan, Angelo M De Marzo, Justin Hwang, Emmanuel S Antonarakis
Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN, USA., Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD, USA., Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA., Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA., Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN, USA. .