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Increased tumor-infiltrating lymphocyte density is associated with favorable outcomes in a comparative study of canine histiocytic sarcoma

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Abstract

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 allude to the immunogenicity of this disease in both species, highlighting the potential for their successful treatment with immunotherapy. 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 that were previously diagnosed with localized HS and treated with curative-intent tumor resection with or without adjuvant chemotherapy. As in humans, assessment of TIL in 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. NanoString transcriptional analyses revealed increased T cell and antigen presentation transcripts associated with prolonged survival in canine pulmonary HS and a decreased tumor immunogenicity profile associated with shorter survivals in splenic HS. 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 preclinically appraise the efficacy and tolerability of anti-cancer immunotherapies for HS.

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Acknowledgements

The authors thank Dr. Leslie King for manuscript review and editing.

Funding

This study was conducted using internal funds provided to Jennifer A Lenz, Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine; internal funds to Robert G Maki Department of Medicine, Perelman School of Medicine, University of Pennsylvania and NCI funding supporting Matthew J Atherton (K08CA252619). 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).

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Authors and Affiliations

  1. Department of Clinical Sciences and Advanced Medicine, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Jennifer A. Lenz & Matthew J. Atherton

  2. Department of Pathobiology, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Charles-Antoine Assenmacher, Amy C. Durham & Enrico Radaelli

  3. Department of Veterinary Clinical Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA

    Victoria Costa

  4. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Katie Louka & Paul J. Zhang

  5. Metropolitan Veterinary Associates, Norristown, PA, USA

    Suzanne Rau

  6. Department of Statistics, University of Wisconsin-Madison, Madison, WI, USA

    Nicholas S. Keuler

  7. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Robert G. Maki

  8. Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, USA

    Matthew J. Atherton

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  1. Jennifer A. Lenz
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Contributions

JAL and MJA were responsible for conceptualization. JAL, CAA, ER and MJA performed methodology. JAL, CAA, VC, KL, SR, NSK, PJZ, RGM, ACD and MJA performed formal analysis and investigation. JAL, CAA and MJA were responsible for writing—original draft preparation. JAL, CAA, NSK, ACD, ER and MJA were responsible for writing—review and editing. JAL, RGM and MJA performed funding acquisition. JAL, CAA, KL, PJZ, RGM, ACD, ER and MJA collected resources. JAL and MJA performed supervision.

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Correspondence to Jennifer A. Lenz or Matthew J. Atherton.

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Précis: Human and canine histiocytic sarcoma biopsies were analyzed for T cell infiltrates. Increased density of tumor-infiltrating lymphocytes was associated with improved outcomes following curative-intent treatment.

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CD3, GZB and FOXP3 TIL densities for 18 dogs with spontaneous HS.

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262_2021_3033_MOESM2_ESM.pdf

CD3 densities in human and canine HS. Data mean ± SD, p-values calculated using two-tailed Mann-Whitney U tests. Histiocytic sarcoma, HS.

Supplementary file2 (PDF 101 KB)

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Lenz, J.A., Assenmacher, CA., Costa, V. et al. Increased tumor-infiltrating lymphocyte density is associated with favorable outcomes in a comparative study of canine histiocytic sarcoma. Cancer Immunol Immunother 71, 807–818 (2022). https://doi.org/10.1007/s00262-021-03033-z

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