Peripheral blood mononuclear cell gene expression signatures predict long-term survivorship in canine DLBCL

TL;DR

Gene expression patterns in blood cells of dogs with lymphoma can predict survival outcomes and treatment response.

Contribution

Identification of PBMC gene signatures that predict early relapse and long-term survival in canine DLBCL.

Findings

Elevated interferon-stimulated genes and immune skewing genes correlate with early relapse in dogs with DLBCL.

CD1E and CCL14 are elevated in long-term survivors, suggesting protective immune signatures.

TBHD, NPNT, and ISG20 are elevated in short-term survivors, indicating potential biomarkers for poor prognosis.

Abstract

Pet dogs spontaneously develop a form of diffuse large B cell lymphoma (DLBCL) that recapitulates many of the features of double hit (MYC/BCL2) human DLBCL. We recently completed a clinical trial in dogs with DLBCL using a combination of canine anti-CD20 antibody and low dose doxorubicin followed by one of three small molecule immune-modulating agents (KPT-9274, TAK-981 or RV1001). Clinical outcomes and tumor specific biomarkers of response from these dogs have been previously reported. In this study, we used the NanoString Canine IO panel to assess dynamic changes in gene counts from peripheral blood mononuclear cells (PBMCs) collected longitudinally from these from dogs over the course of their treatment to identify immune correlates associated with early relapse versus long-term survivorship. Increases in interferon-stimulated gene (ISG) signatures and immune skewing genes [CCR9, CD209 (DC-SIGN), CMKLR and DDX58 (RIG-I)] were associated with shorter (< 400 day) survival times and early relapse. In contrast, CD1E and CCL14 were elevated post-immunotherapy in long-term (> 400 day) survivors, suggesting that these may be associated with protective immune signatures. Examining genes that were expressed in short- versus long-term survivors early on in the treatment regimen identified TBHD, NPNT and ISG20 as elevated in dogs with shorter survival times at day 7. To facilitate point-of-care PBMC gene expression testing that could be used to distinguish those dogs likely to require more intensive treatment regimens in advance of relapse, we developed qPCR assays for TBHD, NPNT and ISG20. Together these data provide proof of principle that biomarker interrogation in PBMCs can help predict early relapse and poor responders to inform clinical management of DLBCL.

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