10.1158/2326-6074.TUMIMM19-A52 [PMC free article] [PubMed] [CrossRef] [Google Scholar]. metastases, with pre- and post-treatment immunogenomic analyses. loss and DNA homologous repair (HR) mutations may be common in this entity (Mota et al. 2019; Rodriguez et al. 2020); however, relatively few tumors have undergone DNA sequencing to date. Moreover, the immune cell composition of brain metastases from prostate cancer has not previously been described. Here we present a patient with metastatic castration-resistant prostate cancer (mCRPC) with brain metastases, whose tumor was found to have DNA mismatch repair deficiency (dMMR) with few CD8+ tumor-infiltrating lymphocytes (TILs) but abundant macrophages. Given the efficacy of immune checkpoint blockade in cancers of varying primary histology with dMMR (Le et al. 2017), the patient was treated with the anti-PD1 antibody pembrolizumab. We describe the clinical and immunogenomic features of this patient. RESULTS Case Description A 60-yr-old man was found to have a prostate-specific antigen (PSA) level of 15.3 ng/mL and was subsequently diagnosed with localized prostate adenocarcinoma with Gleason score 4 + 5 = 9. He underwent primary external-beam radiotherapy with concurrent androgen-deprivation therapy that was planned for 2 yr. However, 18 mo after radiation was completed, he was found to have a rising PSA level despite castrate levels of testosterone and was deemed to have castration-resistant prostate cancer (CRPC). Imaging studies revealed bone metastases and retroperitoneal lymphadenopathy. He was treated with sipuleucel-T immunotherapy, followed by abiraterone and prednisone, but developed disease progression after 8 mo. At that time, he developed slurred speech and difficulty recalling names and performing complex business planning. Magnetic resonance imaging (MRI) of the brain revealed more than 15 parenchymal brain lesions (Fig. 1A,B). Open in a separate window Figure 1. Parenchymal brain PF-03084014 metastases from prostate cancer. (homozygous deletion with microsatellite instability (MSI-high) and a tumor mutational burden of 25 mutations/Mb, indicating dMMR (Table 1; Supplemental Table S1). The patient’s tumor frameshift mutation burden was 11.25 mutations/Mb, and frameshift mutation proportion was 22%. Immunohistochemistry for the four mismatch repair proteins showed loss of Rabbit polyclonal to COT.This gene was identified by its oncogenic transforming activity in cells.The encoded protein is a member of the serine/threonine protein kinase family.This kinase can activate both the MAP kinase and JNK kinase pathways. MLH1 and its binding partner PMS2, with intact expression of MSH2 and MSH6 (Supplemental Fig. S1). He was noted to have a family history of prostate cancer in his father and breast cancer in his sister; however, germline genetic testing using an 84-gene panel (Invitae) was negative for pathogenic germline mutations. Table 1. Next-generation DNA sequencing of brain tumor specimens (FoundationOne CDx, Cambridge, MA) collected before and after pembrolizumab therapy 0.0001) (Fig. 3A). The density of PD1+ cells also increased post-treatment (= 0.005) (Fig. 3B). Conversely, macrophages decreased from a median density of 176.5 cells/mm2 to 56.2 cells/mm2 (= 0.011) (Figs. 2H, ?H,3C).3C). Of note, assessment of the patient’s prior stereotactic radiosurgery plans showed that the analyzed tumor was not PF-03084014 previously encompassed within the radiation field. Open in a separate window Figure PF-03084014 3. Quantification of cells positive for CD8 ((p.L187P) with high allele frequency (Table 1). encodes IB, which binds and inhibits nuclear localization and transcriptional activity of the NF-B complex, and PF-03084014 its inactivation leads to constitutive NF-B activity (Taniguchi and Karin 2018). However, immunohistochemistry for the NF-B subunit p65 did not show enhanced nuclear localization, indicating that this missense change was probably not inactivating (Supplemental Fig. S2). Therefore, the changes in tumor immune cell composition was attributed to pembrolizumab treatment. Given the clear ongoing extra-CNS response and the suggestion of.