Increased Tumor Infiltrating Lymphocyte Density Is Associated with Favorable Outcomes in a Comparative Study of Canine Histiocytic Sarcoma
2021 VCS Annual Conference
Jennifer Lenz1; Charles-Antoine Assenmacher2; Victoria Costa3; Katie Louka4; Suzanne Rau5; Nicholas Keuler6; Paul Zhang4; Robert Maki7; Amy Durham2; Enrico Radaelli2; Matthew Atherton8
1Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA; 2Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA; 3Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA; 4Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 5Metropolitan Veterinary Associates, Norristown, PA, USA; 6Department of Statistics, University of Wisconsin-Madison, Madison, WI, USA; 7Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; 8Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA
Introduction
Histiocytic sarcoma (HS) is a rare and aggressive tumor in humans with no universally agreed standard of care therapy. Spontaneous canine HS exhibits increased prevalence in specific breeds, shares key genetic and biologic similarities with the human disease, and occurs in an immunocompetent setting. Previous data alludes to the immunogenicity of this disease in both species highlighting the potential for their successful treatment with immunotherapy.
Methods
Immunohistochemical quantification of CD3 tumor infiltrating lymphocytes (TIL) in five cases of human HS revealed variable intra-tumoral T cell infiltration. Due to the paucity of human cases and lack of current model systems in which to appraise associations between anti-tumor immunity and treatment-outcome in HS, we analyzed clinical data and quantified TIL in 18 dogs diagnosed with localized HS and treated with curative-intent tumor resection with or without adjuvant chemotherapy. Transcriptional analyses of canine HS tumors were performed using the NanoString nCounter Canine IO Panel.
Results
As in humans, assessment of TIL in canine HS biopsy tissues taken at diagnosis reveal a spectrum of immunologically “cold” to “hot” tumors. Importantly, we show that increased CD3 and granzyme B TIL are positively associated with favorable outcomes in dogs following surgical resection. Transcriptional analyses confirmed a pro-inflammatory tumor microenvironment in pulmonary HS when compared to splenic HS.
Conclusion
Based on these findings, we propose that spontaneous canine HS is an accessible and powerful novel model to study tumor immunology and will provide a unique platform to appraise the efficacy and tolerability of anti-cancer immunotherapies for HS.
Funding Information
Funding for this study was provided by NCI K08CA252619 (MJA) and internal funds provided to Jennifer A Lenz, Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine and Robert G Maki Department of Medicine, Perelman School of Medicine, University of Pennsylvania. The Penn Vet Comparative Pathology Core is supported by the Abramson Cancer Center Support Grant (P30 CA016520). The scanner used for whole slide imaging and the image analysis software was supported by a NIH Shared Instrumentation Grant (S10 OD023465-01A1).