Magnitude of PD-1, PD-L1 and T Lymphocyte Expression on Tissue from Castration-Resistant Prostate Adenocarcinoma: An Exploratory Analysis

Massari, Francesco; Ciccarese, Chiara; Caliò, Anna; Munari, Enrico; Cima, Luca; Porcaro, Antonio Benito; Novella, Giovanni; Artibani, Walter; Sava, Teodoro; Eccher, Albino; Ghimenton, Claudio; Bertoldo, Francesco; Scarpa, Aldo; Sperandio, Nicola; Porta, Camillo; Bronte, Vincenzo; Chilosi, Marco; Bogina, Giuseppe; Zamboni, Giuseppe; Tortora, Giampaolo; Samaratunga, Hemamali; Martignoni, Guido; Brunelli, Matteo

doi:10.1007/s11523-015-0396-3

Cited by 60 publications

(51 citation statements)

References 41 publications

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“…The purpose of our study was to provide some information of understanding the immune profile of prostate TME, in which we particularly focused on PD‐L1 + tumor‐associated nerves, FoxP3 + T reg cells, CD3 + T lymphocytes and CD8 + T cytotoxic cells. Thus far, various anit‐PD‐L1 antibodies have been used to detect PD‐L1 expressions in prostate cancers in different studies, however, the targeted epitopes, isotypes and sources of different anti–PD‐L1 clones contribute to diverse results published at present . We thus further verified a previously validated clone E1L3N (C‐terminal) with clone E1J2J (N‐terminal), complying with the independent antibody strategy proposed by International Working Group for Antibody Validation (IWGAV) …”

Section: Introductionsupporting

confidence: 57%

“…Using clone EPR1161(2) (Abcam) and clone 015 (Sino Biological), two independent investigations reported that high positive rates of PD‐L1 were found on primary prostate tumor cells and CRPC cells in tissue microarrays, respectively . However, when detecting with clone E1L3N, our data revealed that only one out of 73 prostate cancer specimens had histologic evidence of PD‐L1 cell surface membrane staining and none of the 7 CRPC samples showed tumor cell positive (Figs.…”

Section: Resultsmentioning

confidence: 69%

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Expression of PD‐L1 in tumor‐associated nerves correlates with reduced CD8⁺ tumor‐associated lymphocytes and poor prognosis in prostate cancer

Han

Liang

et al. 2019

Intl Journal of Cancer

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To investigate immune profile consisting of stromal PD‐L1 expression, inhibitory or non‐T‐cell inflamed tumor microenvironment that may predict response to anti‐PD‐L1/PD‐1 immunotherapy in prostate cancer, we validated the specificity of a PD‐L1 monoclonal antibody (E1L3N) and identified PD‐L1 specific expression in prostatic stromal nerve cells. PD‐L1 expression was analyzed in 73 primary prostate cancers and 7 castration‐resistant prostate cancers (CRPC) by immunohistochemistry (IHC) and resulting data from primary prostate cancers were correlated with tumor‐associated lymphocytes (TALs), clinicopathological characteristics and clinical outcome. PD‐L1 was expressed in the tumor cells in only one primary prostate cancer case and none of the CRPC. However, PD‐L1 was frequently observed in the nerve branches in the tumor‐associated stroma (69 of 73 cases, 94.5%), supported by colocalization with axonal marker PGP9.5. FoxP3‐, CD3‐ and CD8‐positive T lymphocytes were observed in 74.6% (47/63), 98.4% (62/63) and 100% (61/61) of the cases, respectively. The density of PD‐L1+ tumor‐associated nerves (TANs) was inversely correlated with that of CD8+ TALs. Higher density of PD‐L1+ TANs was significantly associated with biochemical recurrence (BCR) in Kaplan–Meier survival analysis (p = 0.016). In both univariate and multivariate Cox analysis, the density of PD‐L1+ TANs was independently prognostic of BCR. In conclusion, PD‐L1 expression is rare in prostate tumor cells but prevalent in TANs and negatively correlated with CD8+ TALs. Neuro‐immunological interaction may be a contribution to immune‐suppressive microenvironment. Combinatorial treatment regimen designs to neural PD‐L1 and TALs should be warranted in future clinical application of anti‐PD‐L1/PD‐1 immunotherapy in prostate cancer.

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Section: Introductionsupporting

confidence: 57%

Section: Resultsmentioning

confidence: 69%

Expression of PD‐L1 in tumor‐associated nerves correlates with reduced CD8⁺ tumor‐associated lymphocytes and poor prognosis in prostate cancer

Han

Liang

et al. 2019

Intl Journal of Cancer

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“…Its binding to specific ligands (PD-1 ligands), expressed on inhibitory cell lineages and tumor cells, promotes reversible CTL anergy and, on the long term, induces antigenspecific CTL exhaustion. 12,[60][61][62] This event represents a major mechanism of tumor escape and acquired tumor cell resistance to the immune-effectors. More recently, the clinical development of mAbs to PD-1, such as Nivolumab and Pembrolizumab, has given a strong pulse to the design of cancer immunotherapy trials also outside the malignant melanoma area.…”

Section: Discussionmentioning

confidence: 99%

Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse

Nardone

Botta

Caraglia

et al. 2016

Cancer Biology & Therapy

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Tumor immunologic microenvironment is strongly involved in tumor progression and the presence of tumor infiltrating lymphocytes (TIL) with different phenotypes has been demonstrated to be of prognostic relevance in different malignancies. We investigated whether TIL infiltration of tumor tissues could also predict the outcome of prostate cancer patients. To this end, we carried out a retrospective analysis correlating the outcome of locally advanced prostate cancer patients undergone salvage radiotherapy upon relapse after radical surgery with the infiltration by different TIL populations. Twenty-two patients with resectable prostate cancer, with a mean age of 67 (C/¡3.93) years, who received salvage radiotherapy with a mean of 69.66 (C/¡ 3.178) Gy in 8 weeks, between June 1999 and January 2009 and with a median follow up of 123 (C/¡ 55.82) months, were enrolled in this study. We evaluated, by immunohistochemistry, the intratumoral ( t ) and peripheral stroma ( p ) infiltration by CD45, CD3, CD4, CD8, CCR7, FoxP3 or PD-1-positive cells on tumor samples taken at the diagnosis ( d ) and relapse times ( R ). We correlated these variables with patients' biochemical progression free survival (bPFS), post-radiotherapy progression free survival (PFS), and overall survival (OS). Substantial changes in the rate of TIL subsets were found between the first and the second biopsy with progressive increase in CD4, CCR7, FoxP3, PD-1 C cells. Our analysis revealed that higher CD8 p,RC and lower PD-1 RC TIL scores correlated to a longer bPFS. Higher CD8 p,RC and CCR7 t,RC TIL scores and lower CD45 p,RC and FoxP3 p,RC TIL scores correlated to a prolonged PFS and OS. These results suggest that the immunological microenvironment of primary tumor is strictly correlated with patient outcome and provide the rationale for immunological treatment of prostate cancer.

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“…A signature defining a potential response to anti-PD-1 therapy has not been developed, such as quantifying and correlating PD-1/PD-L1 expression to response or associating response for patients with specific prior treatments. The data regarding expression of PD-1/PD-L1 in prostate cancer is conflicting [60, 61,62]. Furthermore, it is possible that therapy for prostate cancer (such as antiandrogens) results in relative immunosuppression [63] that theoretically may blunt anti-PD-1 response.…”

Section: Treatment Opportunities For Homologous Recombination-deficiementioning

confidence: 99%

Treatment strategies for DNA repair-deficient prostate cancer

Teply

Antonarakis

2017

Expert Review of Clinical Pharmacology

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Introduction: Common recurrent genetic alterations have been identified in prostate cancer through comprehensive sequencing efforts, and the prevalence of mutations in DNA repair pathway genes in patients with advanced and metastatic disease approaches 20–25%. Identification of these underlying DNA repair defects may present unique treatment opportunities for patients, both in terms of standard-of-care treatments and selected investigational agents. Areas Covered: We review our current understanding of the genomic landscape of prostate cancer, with special attention to alterations in DNA repair pathway genes in metastatic castration-resistant disease. For patients with tumors deficient in homologous recombination repair, potential opportunities for treatment include platinum chemotherapy, poly(ADP) ribose polymerase (PARP) inhibitors, bipolar androgen therapy, and maybe immune checkpoint blockade therapy. In addition, tumors with mismatch repair defects (i.e. microsatellite instability) may be particularly susceptible to checkpoint blockade immunotherapy. Expert Commentary: We anticipate that genomic profiling of tumors will become necessary to guide treatment of advanced prostate cancer treatment in the coming years. Work is needed to define the optimal tissue to test, and to define the national history of tumors with specific genetic defects. The prognostic and therapeutic importance of germline vs somatic DNA repair alterations, and mono-allelic vs bi-allelic inactivation, also remains unclear. Finally, optimal strategies to sequence or combine targeted agents for these patients with ‘actionable’ mutations are now needed.

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Magnitude of PD-1, PD-L1 and T Lymphocyte Expression on Tissue from Castration-Resistant Prostate Adenocarcinoma: An Exploratory Analysis

Abstract: Approximately 19 % of patients in our series showed simultaneous high PD-1/PD-L1 immunoscores, and were the best candidates for receiving targeted anti-PD-1/PD-L1 immunotherapy, as determined using a tissue based rationale.

Cited by 60 publications

References 41 publications

Expression of PD‐L1 in tumor‐associated nerves correlates with reduced CD8⁺ tumor‐associated lymphocytes and poor prognosis in prostate cancer

Expression of PD‐L1 in tumor‐associated nerves correlates with reduced CD8⁺ tumor‐associated lymphocytes and poor prognosis in prostate cancer

Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse

Treatment strategies for DNA repair-deficient prostate cancer

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Magnitude of PD-1, PD-L1 and T Lymphocyte Expression on Tissue from Castration-Resistant Prostate Adenocarcinoma: An Exploratory Analysis

Abstract: Approximately 19 % of patients in our series showed simultaneous high PD-1/PD-L1 immunoscores, and were the best candidates for receiving targeted anti-PD-1/PD-L1 immunotherapy, as determined using a tissue based rationale.

Cited by 60 publications

References 41 publications

Expression of PD‐L1 in tumor‐associated nerves correlates with reduced CD8+ tumor‐associated lymphocytes and poor prognosis in prostate cancer

Expression of PD‐L1 in tumor‐associated nerves correlates with reduced CD8+ tumor‐associated lymphocytes and poor prognosis in prostate cancer

Tumor infiltrating T lymphocytes expressing FoxP3, CCR7 or PD-1 predict the outcome of prostate cancer patients subjected to salvage radiotherapy after biochemical relapse

Treatment strategies for DNA repair-deficient prostate cancer

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Product

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Expression of PD‐L1 in tumor‐associated nerves correlates with reduced CD8⁺ tumor‐associated lymphocytes and poor prognosis in prostate cancer

Expression of PD‐L1 in tumor‐associated nerves correlates with reduced CD8⁺ tumor‐associated lymphocytes and poor prognosis in prostate cancer