Increased programmed death ligand (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) expression is associated with metastasis and poor prognosis in malignant canine mammary gland tumours

Ariyarathna, H.A.C.K.; Na, Thomson; Aberdein, Danielle; Perrott, Matthew R.

doi:10.1016/j.vetimm.2020.110142

Cited by 20 publications

(19 citation statements)

References 40 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent studies suggest that the PD-1/PD-L1 axis also plays a pivotal role in a wide range of canine malignancies, including oral melanoma, osteosarcoma, hemangiosarcoma, mast cell tumor, and mammary carcinoma [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ]. In canine B-cell lymphoma, a higher expression of PD-L1 by neoplastic lymphocytes compared to normal B-cells was demonstrated by flow-cytometry, and an increased in vitro drug resistance was associated with PD-1 and PD-L1 protein expression [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

Prognostic Value of PD-L1, PD-1 and CD8A in Canine Diffuse Large B-Cell Lymphoma Detected by RNAscope

Aresu

Marconato

Martini

et al. 2021

Veterinary Sciences

View full text Add to dashboard Cite

Immune checkpoints are a set of molecules dysregulated in several human and canine cancers and aberrations of the PD-1/PD-L1 axis are often correlated with a worse prognosis. To gain an insight into the role of immune checkpoints in canine diffuse large B-cell lymphoma (cDLBCL), we investigated PD-L1, PD-1 and CD8A expression by RNAscope. Results were correlated with several clinico-pathological features, including treatment, Ki67 index and outcome. A total of 33 dogs treated with chemotherapy (n = 12) or chemoimmunotherapy with APAVAC (n = 21) were included. PD-L1 signal was diffusely distributed among neoplastic cells, whereas PD-1 and CD8A were localized in tumor infiltrating lymphocytes. However, PD-1 mRNA was also retrieved in tumor cells. An association between PD-L1 and PD-1 scores was identified and a higher risk of relapse and lymphoma-related death was found in dogs treated with chemotherapy alone and dogs with higher PD-L1 and PD-1 scores. The correlation between PD-L1 and PD-1 is in line with the mechanism of immune checkpoints in cancers, where neoplastic cells overexpress PD-L1 that, in turn, binds PD-1 receptors in activated TIL. We also found that Ki67 index was significantly increased in dogs with the highest PD-L1 and PD-1 scores, indirectly suggesting a role in promoting tumor proliferation. Finally, even if the biological consequence of PD-1+ tumor cells is unknown, our findings suggest that PD-1 intrinsic expression in cDLBCL might contribute to tumor growth escaping adaptive immunity.

show abstract

Section: Discussionmentioning

confidence: 99%

Prognostic Value of PD-L1, PD-1 and CD8A in Canine Diffuse Large B-Cell Lymphoma Detected by RNAscope

Aresu

Marconato

Martini

et al. 2021

Veterinary Sciences

View full text Add to dashboard Cite

show abstract

“…The programmed death receptor (PD-1) and its ligand (PD-L1) have been studied in human cancers with several reports also in canine cancers; revealing that canines appear to be an excellent immunological model for the disease. [23][24][25][26][27][28][29][30][31][32][33][34] The PD-1 receptor is a transmembrane protein that is part of the B7-H1 immunoglobulin superfamily and is present on many immune cells. In particular, PD-1 is commonly expressed on T lymphocytes.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of lymphocyte‐specific programmed cell death protein 1 receptor expression and cytokines in blood and urine in canine urothelial carcinoma patients

Pinard

Stegelmeier

Bridle

et al. 2021

Vet Comparative Oncology

View full text Add to dashboard Cite

Urothelial carcinoma (UC) is the most common urinary tumour in dogs. Despite a range of treatment options, prognosis remains poor in dogs. In people, breakthroughs with checkpoint inhibitors have established new standards of care for muscle‐invasive bladder cancer patients and elevated levels of programmed cell death protein 1 (PD‐1) suggest immune checkpoint blockade may be a novel target for therapy. The goal of this study was to determine if canine UC patients express elevated levels of lymphocyte‐specific PD‐1 and/or urinary cytokine biomarkers compared to healthy dogs. Paired blood and urine were evaluated in 10 canine UC patients, five cystitis patients and 10 control dogs for lymphocyte‐specific PD‐1 expression via flow cytometry and relative cytokine expression. In UC patients, PD‐1 expression was significantly elevated on CD8+ lymphocytes in urine samples. UC patients had a higher CD4:CD8 ratio in their urine compared to healthy dogs, however, there was no significant variation in the CD8:Treg ratio between any group. Cystitis patients had significantly elevated levels of CD4+ T cells, CD8+ T cells and Tregs in their blood samples compared to UC patients and healthy dogs. Cytokine analysis demonstrated significant elevations in urinary cytokines (granulocyte‐macrophage colony‐stimulating factor, interferon‐gamma [IFN‐γ], interleukin (IL)‐2, IL‐6 IL‐7, IL‐8 and IL‐15, IP‐10, KC‐like, IL‐18, monocyte chemoattractant protein‐1 and tumour necrosis factor‐alpha). Several of these cytokines have been previously correlated with both lymphocyte‐specific PD‐1 expression (IFN‐γ, IL‐2, IL‐7 and IL‐15) in muscle‐invasive urothelial carcinoma in humans. Our results provide evidence of urinary lymphocyte PD‐1 expression and future studies could elucidate whether veterinary UC patients will respond favourably to anti‐PD‐1 immune checkpoint inhibitor therapy.

show abstract

“…Ninety to 100% of COMs express PD-L1 [126][127][128], possibly in response to IFNγ [126] and modulated by interaction with CD3+ T cells [120], with membrane expression maintained by CMTM6 (CKLF-like MARVEL transmembrane domain protein 6) [129]. Tumour cell expression of PD-L1 is a negative prognostic indicator in human oncology, with similar findings established for PD-L1 expression in canine malignant mammary gland tumours [130]. Critically, PD-1 mediated immune suppression is reversible, with promising clinical application of monoclonal antibodies to block the interaction between PD-1 and PD-L1 [128].…”

Section: Tumour Infiltrating Lymphocytes and Mechanisms Of Immune Tolerancementioning

confidence: 60%

A Comparative View on Molecular Alterations and Potential Therapeutic Strategies for Canine Oral Melanoma

Hardwick

2021

Veterinary Sciences

View full text Add to dashboard Cite

Canine oral melanoma (COM) is a highly aggressive tumour associated with poor prognosis due to metastasis and resistance to conventional anti-cancer therapies. As with human mucosal melanoma, the mutational landscape is predominated by copy number aberrations and chromosomal structural variants, but differences in study cohorts and/or tumour heterogeneity can lead to discordant results regarding the nature of specific genes affected. This review discusses somatic molecular alterations in COM that result from single nucleotide variations, copy number changes, chromosomal rearrangements, and/or dysregulation of small non-coding RNAs. A cross-species comparison highlights notable recurrent aberrations, and functionally grouping dysregulated proteins reveals unifying biological pathways that may be critical for oncogenesis and metastasis. Finally, potential therapeutic strategies are considered to target these pathways in canine patients, and the benefits of collaboration between science, medical, and veterinary communities are emphasised.

show abstract

Increased programmed death ligand (PD-L1) and cytotoxic T-lymphocyte antigen-4 (CTLA-4) expression is associated with metastasis and poor prognosis in malignant canine mammary gland tumours

Cited by 20 publications

References 40 publications

Prognostic Value of PD-L1, PD-1 and CD8A in Canine Diffuse Large B-Cell Lymphoma Detected by RNAscope

Prognostic Value of PD-L1, PD-1 and CD8A in Canine Diffuse Large B-Cell Lymphoma Detected by RNAscope

Evaluation of lymphocyte‐specific programmed cell death protein 1 receptor expression and cytokines in blood and urine in canine urothelial carcinoma patients

A Comparative View on Molecular Alterations and Potential Therapeutic Strategies for Canine Oral Melanoma

Contact Info

Product

Resources

About