Divergent immune microenvironments in two tumor nodules from a patient with mismatch repair-deficient prostate cancer
© 2024. The Author(s)..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:9 |
|---|---|
| Enthalten in: |
NPJ genomic medicine - 9(2024), 1 vom: 22. Jan., Seite 7 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Bergom, Hannah E [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
|---|
| Anmerkungen: |
Date Revised 10.02.2024 published: Electronic Citation Status PubMed-not-MEDLINE |
|---|
| doi: |
10.1038/s41525-024-00392-1 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM367440253 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM367440253 | ||
| 003 | DE-627 | ||
| 005 | 20240210233147.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240123s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41525-024-00392-1 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1287.xml |
| 035 | |a (DE-627)NLM367440253 | ||
| 035 | |a (NLM)38253539 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Bergom, Hannah E |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Divergent immune microenvironments in two tumor nodules from a patient with mismatch repair-deficient prostate cancer |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Revised 10.02.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 700 | 1 | |a Sena, Laura A |e verfasserin |4 aut | |
| 700 | 1 | |a Day, Abderrahman |e verfasserin |4 aut | |
| 700 | 1 | |a Miller, Benjamin |e verfasserin |4 aut | |
| 700 | 1 | |a Miller, Carly D |e verfasserin |4 aut | |
| 700 | 1 | |a Lozada, John R |e verfasserin |4 aut | |
| 700 | 1 | |a Zorko, Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a Wang, Jinhua |e verfasserin |4 aut | |
| 700 | 1 | |a Shenderov, Eugene |e verfasserin |4 aut | |
| 700 | 1 | |a Lobo, Francisco Pereira |e verfasserin |4 aut | |
| 700 | 1 | |a Caramella-Pereira, Fernanda |e verfasserin |4 aut | |
| 700 | 1 | |a Marchionni, Luigi |e verfasserin |4 aut | |
| 700 | 1 | |a Drake, Charles G |e verfasserin |4 aut | |
| 700 | 1 | |a Lotan, Tamara |e verfasserin |4 aut | |
| 700 | 1 | |a De Marzo, Angelo M |e verfasserin |4 aut | |
| 700 | 1 | |a Hwang, Justin |e verfasserin |4 aut | |
| 700 | 1 | |a Antonarakis, Emmanuel S |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t NPJ genomic medicine |d 2016 |g 9(2024), 1 vom: 22. Jan., Seite 7 |w (DE-627)NLM262254506 |x 2056-7944 |7 nnns |
| 773 | 1 | 8 | |g volume:9 |g year:2024 |g number:1 |g day:22 |g month:01 |g pages:7 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41525-024-00392-1 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 9 |j 2024 |e 1 |b 22 |c 01 |h 7 | ||