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

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

doi:10.1038/s41525-024-00392-1

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

NPJ Genom Med. 2024 Jan 22;9(1):7. doi: 10.1038/s41525-024-00392-1.

Authors

Hannah E Bergom^#^{1

2}, Laura A Sena^#³, Abderrahman Day^#^{1

2

4}, Benjamin Miller¹, Carly D Miller¹, John R Lozada^{1

2

5}, Nicholas Zorko^{1

2

5}, Jinhua Wang^{1

4

5}, Eugene Shenderov^{6

7}, Francisco Pereira Lobo^{3

8}, Fernanda Caramella-Pereira³, Luigi Marchionni⁹, Charles G Drake^{3

10}, Tamara Lotan³, Angelo M De Marzo³, Justin Hwang^{1

2

5}, Emmanuel S Antonarakis^{11

12

13}

Affiliations

¹ Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN, USA.
² Division of Hematology, Oncology and Transplantation, University of Minnesota-Twin Cities, Minneapolis, MN, USA.
³ Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins, Baltimore, MD, USA.
⁴ Institute for Health Informatics, University of Minnesota, Minneapolis, MN, USA.
⁵ Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
⁶ Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁷ The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, MD, USA.
⁸ Universidade Federal de Minas Gerais, Belo Horizonte, MG, Brazil.
⁹ Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY, USA.
¹⁰ Janssen Research and Development, LLC, Springhouse, PA, USA.
¹¹ Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN, USA. [email protected].
¹² Division of Hematology, Oncology and Transplantation, University of Minnesota-Twin Cities, Minneapolis, MN, USA. [email protected].
¹³ Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA. [email protected].

^# Contributed equally.

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.

Abstract

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