Immune landscape of human prostate cancer: immune evasion mechanisms and biomarkers for personalized immunotherapy

Abstract

Background Despite recent advances in cancer immunotherapy, the efficacy of these therapies for the treatment of human prostate cancer patients is low due to the complex immune evasion mechanisms (IEMs) of prostate cancer and the lack of predictive biomarkers for patient responses. Methods To understand the IEMs in prostate cancer and apply such understanding to the design of personalized immunotherapies, we analyzed the RNA-seq data for prostate adenocarcinoma from The Cancer Genome Atlas (TCGA) using a combination of biclustering, differential expression analysis, immune cell typing, and machine learning methods. Results The integrative analysis identified eight clusters with different IEM combinations and predictive biomarkers for each immune evasion cluster. Prostate tumors employ different combinations of IEMs. The majority of prostate cancer patients were identified with immunological ignorance (89.8%), upregulated cytotoxic T lymphocyte-associated protein 4 (CTLA4) (58.8%), and upregulated decoy receptor 3 (DcR3) (51.6%). Among patients with immunologic ignorance, 41.4% displayed upregulated DcR3 expression, 43.26% had upregulated CTLA4, and 11.4% had a combination of all three mechanisms. Since upregulated programmed cell death 1 (PD-1) and/or CTLA4 often co-occur with other IEMs, these results provide a plausible explanation for the failure of immune checkpoint inhibitor monotherapy for prostate cancer. Conclusion These findings indicate that human prostate cancer specimens are mostly immunologically cold tumors that do not respond well to mono-immunotherapy. With such identified biomarkers, more precise treatment strategies can be developed to improve therapeutic efficacy through a greater understanding of a patient’s immune evasion mechanisms.

Transcriptional landscape of PTEN loss in primary prostate cancer

“…Remarkably, despite the loss of PTEN being associated with higher expression of the immune checkpoint gene programmed death ligand-1 ( PD-L1 ) in several cancer types [ 76 , 77 ], this is not true in PCa [ 78 ]. It has been shown that PCa employ different combinations of immune evasion mechanisms such as immunological ignorance, upregulated cytotoxic T lymphocyte-associated protein 4, and upregulated decoy receptor 3 [ 79 ]. So far, current immunotherapeutic interventions, such as PD-1 blockade, in PCa have not been successful.…”

Immunophenotype Rearrangement in Response to Tumor Excision May Be Related to the Risk of Biochemical Recurrence in Prostate Cancer Patients

“…We studied the rearrangements of the immune system at one and three months in order to avoid early stimulus of postoperative stress (stress hormone ejection, WBC, and cytokine fluctuations). The high immunogenicity of PCa [19] offers a unique platform to study tumor excision effects on sparing or even boosting postoperative immunosurveillance function. However, the specific markers indicating immune rearrangement in progressing PCa or following RP are yet to be elucidated [20].…”

Prostate Cancer in 2021: Novelties in Prognostic and Therapeutic Biomarker Evaluation

“…Bou-Dargham et al identified eight different immune evasion clusters, in which the majority of the clustered PCa patients (around 90%) exhibited immunological ignorance that can result from the absence of tumor-specific antigens that activate the immune system, or from the failure of antigen-presenting cells to recognize cancer antigens. Interestingly, they also reported a series of biomarkers that could predict responses to various immunotherapies CD48, SP140, KIRREL, RHOB, FBXO17, ANAPC1, EGFR, SOCS3, ALOX15, and UBR2 [ 43 ].…”