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The requirement for immune infiltration and organization in the tumor microenvironment for successful immunotherapy in prostate cancer.

ABSTRACT: Immunotherapy-particularly immune checkpoint blockade-has seen great success in many tumor types. However, checkpoint-based therapies have not demonstrated high levels of success in prostate cancer, and there is much to be learned from both the successes and failures of these treatments. Here we review the evidence that composition of infiltrating immune cells in the tumor microenvironment is fundamental to the response to immunotherapy. Additionally, we discuss the emerging idea that the organization of these immune cells may also be crucial to this response. In prostate cancer, the composition and organization of the tumor immune microenvironment are preeminent topics of discussion and areas of important future investigation.

SUBMITTER: Jansen CS

PROVIDER: S-EPMC6513714 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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The requirement for immune infiltration and organization in the tumor microenvironment for successful immunotherapy in prostate cancer.

Jansen Caroline S CS Prokhnevska Nataliya N Kissick Haydn T HT

Urologic oncology 20181113 8

Immunotherapy-particularly immune checkpoint blockade-has seen great success in many tumor types. However, checkpoint-based therapies have not demonstrated high levels of success in prostate cancer, and there is much to be learned from both the successes and failures of these treatments. Here we review the evidence that composition of infiltrating immune cells in the tumor microenvironment is fundamental to the response to immunotherapy. Additionally, we discuss the emerging idea that the organi ...[more]

PMID: 30446449

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Project description:BACKGROUND:Clinical trials have shown the ability of therapeutic vaccines to generate immune responses to tumor-associated antigens (TAAs). What is relatively less known is if this translates into immune-cell (IC) infiltration into the tumor microenvironment. This study examined whether neoadjuvant prostate-specific antigen (PSA)-targeted vaccination with PROSTVAC could induce T-cell immunity, particularly at the tumor site. METHODS:An open-label, phase II study of neoadjuvant PROSTVAC vaccine enrolled 27 patients with localized prostate cancer awaiting radical prostatectomy (RP). We evaluated increases in CD4 and CD8 T-cell infiltrates (RP tissue vs baseline biopsies) using a six-color multiplex immunofluorescence Opal method. Antigen-specific responses were assessed by intracellular cytokine staining after in vitro stimulation of peripheral blood mononuclear cells with overlapping 15-mer peptide pools encoding the TAAs PSA, brachyury and MUC-1. RESULTS:Of 27 vaccinated patients, 26 had matched prevaccination (biopsy) and postvaccination (RP) prostate samples available for non-compartmentalized analysis (NCA) and compartmentalized analysis (CA). Tumor CD4 T-cell infiltrates were significantly increased in postvaccination RP specimens compared with baseline biopsies by NCA (median 176/mm² vs 152/mm²; IQR 136-317/mm² vs 69-284/mm²; p=0.0249; median ratio 1.20; IQR 0.64-2.25). By CA, an increase in both CD4 T-cell infiltrates at the tumor infiltrative margin (median 198/mm² vs 151/mm²; IQR 123-500/mm² vs 85-256/mm²; p=0.042; median ratio 1.44; IQR 0.59-4.17) and in CD8 T-cell infiltrates at the tumor core (median 140/mm² vs 105/mm²; IQR 91-175/mm² vs 83-163/mm²; p=0.036; median ratio 1.25; IQR 0.88-2.09) were noted in postvaccination RP specimens compared with baseline biopsies. A total of 13/25 patients (52%) developed peripheral T-cell responses to any of the three tested TAAs (non-neoantigens); five of these had responses to more than one antigen of the three evaluated. CONCLUSION:Neoadjuvant PROSTVAC can induce both tumor immune response and peripheral immune response. TRIAL REGISTRATION NUMBER:NCT02153918.

Project description:Objective: Because of the modest immunotherapeutic response among ovarian carcinoma (OC) patients, it is significant to evaluate antitumor immune response and develop more effective precision immunotherapeutic regimens. Here, this study aimed to determine diverse immune subtypes of OC. Methods: This study curated the expression profiles of prognostic immunologically relevant genes and conducted consensus clustering analyses for determining immune subtypes among OC patients in TCGA cohort. With Boruta algorithm, characteristic genes were screened for conducting an immune scoring system through principal component analysis algorithm. The single-sample gene set enrichment analysis and ESTIAMTE methods were adopted for quantifying the immune infiltrates and responses to chemotherapeutic agents were estimated with pRRophetic algorithm. Two immunotherapeutic cohorts were used for investigating the efficacy of immune score in predicting therapeutic benefits. Results: Two immune subtypes were conducted among 377 OC patients. Immune subtype 2 was characterized by worse clinical prognosis, more frequent genetic variations and mutations, enhanced immune infiltrates, and increased expression of MHC molecules and programmed cell death protein 1/programmed death ligand 1 (PD-1/PD-L1). In total, 30 prognosis-relevant characteristic immune subtype-derived genes were identified for constructing the immune score of OC patients. High immune score was linked with more dismal prognosis, decreased immune infiltrations, and expression of MHC molecules. High immune score presented favorable sensitivity to doxorubicin and vinorelbine and reduced sensitivity to cisplatin. In addition, immune score possessed the potential in predicting benefits from anti-PD-1/PD-L1 therapy. Conclusion: Collectively, our findings propose two complex and diverse immune subtypes of OC. Quantitative assessment of immune subtypes in individual patients strengthens the understanding of tumor microenvironment features and promotes more effective immunotherapeutic regimens.

Dataset Information

The requirement for immune infiltration and organization in the tumor microenvironment for successful immunotherapy in prostate cancer.

Publications

The requirement for immune infiltration and organization in the tumor microenvironment for successful immunotherapy in prostate cancer.

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