Checkpoint molecule expression by B and T cell lymphomas in dogs

Hartley, Genevieve; Elmslie, Robyn; Dow, Steven; Guth, Amanda

doi:10.1111/vco.12386

Cited by 30 publications

(31 citation statements)

References 59 publications

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“…There have also been some reports on the PD-1/PD-L1 axis in dogs with different malignancies [ 13 , 14 , 33 ]. Recently, high expression of PD-1 on tumor infiltrating T cells was reported in dogs with B and T cell lymphoma [ 34 ]. In this study, significantly higher expression of PD-1 was observed on CD4+ T cells obtained from LNCs from dogs with lymphoma, and CD8+ T cells tended to up-regulate these molecules.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of costimulatory molecules in dogs with B cell high grade lymphoma

et al. 2018

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B cell high grade lymphoma is the most common hematopoietic malignancy in dogs. Although the immune checkpoint molecules, programmed death-1 (PD-1) and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), and immune checkpoint inhibitors have been evaluated for the treatment of various human lymphoid malignancies, the expression of those molecules and their relationship with prognosis remain unknown in canine lymphoma. The objective of this study was to evaluate the expression of costimulatory molecules on peripheral blood lymphocytes and tumor infiltrating lymphocytes, in addition to associated ligand expression in the lymph nodes of patients with B cell multicentric high grade lymphoma. Eighteen patients diagnosed with B cell high grade lymphoma and nine healthy control dogs were enrolled. Flow cytometric analysis revealed that the expression of PD-1 on CD4+ peripheral and tumor infiltrating lymphocytes and CTLA-4 on CD4+ peripheral lymphocytes was significantly higher in the lymphoma group than in the control group. The expression level of CD80 mRNA was significantly lower in the lymphoma group than in the control group. In contrast, there were no significant differences in PD-L1, PD-L2, and CD86 expression between the groups. Dogs with CTLA-4 levels below the cutoff values, which were determined based on receiver operating characteristic curves, on peripheral CD4+, CD8+, and tumor infiltrating CD4+ lymphocytes had significantly longer survival than dogs with values above the cutoff. Although it is uncertain whether the expression of immune checkpoint molecules affect the biological behavior of canine lymphoma, one possible explanation is that PD-1 and CTLA-4 might be associated with the suppression of antitumor immunity in dogs with B cell high grade lymphoma, particularly through CD4+ T cells.

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Section: Discussionmentioning

confidence: 99%

Evaluation of costimulatory molecules in dogs with B cell high grade lymphoma

et al. 2018

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“…Isotype‐matched, irrelevant antibodies were used at the same concentrations. To identify lymphocyte populations, B cell were identified as CD21 + (APC, clone CA2.1D6) and T cells were identified as CD5 + (FITC, clone YKIX322.3) from Bio‐Rad Laboratories (Hercules, California), as described previously …”

Section: Methodsmentioning

confidence: 99%

Cancer stem cell populations in lymphoma in dogs and impact of cytotoxic chemotherapy

Hartley

Elmslie²,

Murphy

et al. 2018

Vet Comparative Oncology

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Cancer relapse following chemotherapy has been attributed in part to the presence of cancer stem cells (CSC), which drive tumor growth and metastasis and are highly resistant to the effects of cytotoxic chemotherapy. As a result, treatment with cytotoxic chemotherapy selects for drug-resistant CSC populations that eventually drive tumor recurrence. Little is known currently regarding the role of CSC in dogs with lymphoma, nor the impact of chemotherapy on CSC populations. Therefore, we prospectively quantitated CSC populations in dogs with B cell and T cell lymphoma, using tumor aspirates and flow cytometric analysis with a panel of CSC markers. In addition, in vitro studies were done to determine the impact of chemotherapy resistance on the stem cell phenotype and stem cell properties of lymphoma cells. We found that the percentages of tumor cells expressing CSC markers were significantly increased in dogs with B cell lymphoma, compared to B cells from normal lymph nodes. Similar findings were observed in dogs with T cell lymphoma. In vitro studies revealed that lymphoma cells selected for resistance to CHOP chemotherapy had significantly upregulated expression of CSC markers, formed spheroids in culture more readily, and expressed significantly greater aldehyde dehydrogenase activity compared to chemotherapy-sensitive tumor cells. Similar results were observed in tumor samples dogs with relapsed B cell lymphoma. These findings suggest that cytotoxic chemotherapy can lead to a relative enrichment of tumor cells with CSC properties, which may be associated with lymphoma recurrence.

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“…There are multiple reports of the expression of immune checkpoints in InvUC and other cancers in dogs (148)(149)(150)(151)(152)(153)(154)(155)(156)(157). In addition to the well-known checkpoints PD-1, PD-L1, CTLA-4, other checkpoints have been identified in canine InvUC (59, 157).…”

Section: Growing Role For the Dog Model To Drive Advances In Emergingmentioning

confidence: 99%

Naturally-Occurring Invasive Urothelial Carcinoma in Dogs, a Unique Model to Drive Advances in Managing Muscle Invasive Bladder Cancer in Humans

et al. 2020

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There is a great need to improve the outlook for people facing urinary bladder cancer, especially for patients with invasive urothelial carcinoma (InvUC) which is lethal in 50% of cases. Improved outcomes for patients with InvUC could come from advances on several fronts including emerging immunotherapies, targeted therapies, and new drug combinations; selection of patients most likely to respond to a given treatment based on molecular subtypes, immune signatures, and other characteristics; and prevention, early detection, and early intervention. Progress on all of these fronts will require clinically relevant animal models for translational research. The animal model(s) should possess key features that drive success or failure of cancer drugs in humans including tumor heterogeneity, genetic-epigenetic crosstalk, immune cell responsiveness, invasive and metastatic behavior, and molecular subtypes (e.g., luminal, basal). Experimental animal models, while essential in bladder cancer research, do not possess these collective features to accurately predict outcomes in humans. These key features, however, are present in naturally-occurring InvUC in pet dogs. Canine InvUC closely mimics muscle-invasive bladder cancer in humans in cellular and molecular features, molecular subtypes, immune response patterns, biological behavior (sites and frequency of metastasis), and response to therapy. Thus, dogs can offer a highly relevant animal model to complement other models in research for new therapies for bladder cancer. Clinical treatment trials in pet dogs with InvUC are considered a win-win-win scenario; the individual dog benefits from effective treatment, the results are expected to help other dogs, and the findings are expected to translate to better treatment outcomes in humans. In addition, the high breedassociated risk for InvUC in dogs (e.g., 20-fold increased risk in Scottish Terriers) Knapp et al. Canine Bladder Cancer-Translational Model offers an unparalleled opportunity to test new strategies in primary prevention, early detection, and early intervention. This review will provide an overview of canine InvUC, summarize the similarities (and differences) between canine and human InvUC, and provide evidence for the expanding value of this canine model in bladder cancer research.

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Checkpoint molecule expression by B and T cell lymphomas in dogs

Cited by 30 publications

References 59 publications

Evaluation of costimulatory molecules in dogs with B cell high grade lymphoma

Evaluation of costimulatory molecules in dogs with B cell high grade lymphoma

Cancer stem cell populations in lymphoma in dogs and impact of cytotoxic chemotherapy

Naturally-Occurring Invasive Urothelial Carcinoma in Dogs, a Unique Model to Drive Advances in Managing Muscle Invasive Bladder Cancer in Humans

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