Article ; Online: Divergent immune microenvironments in two tumor nodules from a patient with mismatch repair-deficient prostate cancer.
2024 Volume 9, Issue 1, Page(s) 7
Abstract: 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 ... ...
Abstract | 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. |
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Language | English |
Publishing date | 2024-01-22 |
Publishing country | England |
Document type | Journal Article |
ZDB-ID | 2813848-X |
ISSN | 2056-7944 ; 2056-7944 |
ISSN (online) | 2056-7944 |
ISSN | 2056-7944 |
DOI | 10.1038/s41525-024-00392-1 |
Database | MEDical Literature Analysis and Retrieval System OnLINE |
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