Divergent immune microenvironments in two tumor nodules from a patient with mismatch repair-deficient prostate cancer

Patients with prostate cancer (PC) generally do not respond favorably to immune checkpointinhibitors, which may be due to a low abundance of tumor-infiltrating lymphocytes even whenmutational load is high. Here, we identified a patient who presented with high-grade primaryprostate cancer with two adjacent tumor nodules. While both nodules were mismatch repair-deficient (MMRd), exhibited pathogenic MSH2 and MSH6 alterations, had a high tumormutational burden (TMB), and demonstrated high microsatellite instability (MSI), they hadmarkedly distinct immune phenotypes. The first displayed a dense infiltrate of lymphocytes (hotnodule), while the second displayed significantly fewer infiltrating lymphocytes (coldnodule). 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 besub-clonal relative to the hot nodule, suggesting divergent evolution of the cold nodule from thehot nodule. Whole-transcriptome RNA analysis found that the cold nodule demonstrated lowerexpression of genes related to antigen presentation (HLA) and, paradoxically, classical tumorimmune tolerance markers such as PD-L1 (CD274) and CTLA-4. Immune cell deconvolutionsuggested that the hot nodule was enriched not only in CD8+ and CD4+ T lymphocytes, but alsoin M1 macrophages, activated NK cells, and gamma delta T cells compared to the cold nodule. This casehighlights 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 potentialmechanism of adaptive immune evasion in PC.