Comparative Evaluation of Tumor-Infiltrating Lymphocytes in Companion Animals: Immuno-Oncology as a Relevant Translational Model for Cancer Therapy

Abstract

Despite the important role of preclinical experiments to characterize tumor biology and molecular pathways, there are ongoing challenges to model the tumor microenvironment, specifically the dynamic interactions between tumor cells and immune infiltrates. Comprehensive models of host-tumor immune interactions will enhance the development of emerging treatment strategies, such as immunotherapies. Although in vitro and murine models are important for the early modelling of cancer and treatment-response mechanisms, comparative research studies involving veterinary oncology may bridge the translational pathway to human studies. The natural progression of several malignancies in animals exhibits similar pathogenesis to human cancers, and previous studies have shown a relevant and evaluable immune system. Veterinary oncologists working alongside oncologists and cancer researchers have the potential to advance discovery. Understanding the host-tumor-immune interactions can accelerate drug and biomarker discovery in a clinically relevant setting. This review presents discoveries in comparative immuno-oncology and implications to cancer therapy.

Keywords: TILs; canine; comparative oncology; neoplasia.

Figure 1

The immune cellular microenvironment of cancer. Pro-tumorigenic immune cell types include T-regulatory cells (Tregs), M2 macrophages, dendritic cells (type 2), myeloid-derived suppressor cells (MDSCs), T-helper 2 (Th2) cells, and neutrophils (N2). Anti-tumor immune cell types include CD8+ T-cells, T-helper 1 (Th1) cells, neutrophils (N1), dendritic cells (type 1), natural killer (NK), and natural killer T-cells (NKT). These cells, their relative abundance, and microenvironmental signals play a critical role in anti- or protumor activity of cancer cells. Salgado et al., Harmonization of the evaluation of tumor infiltrating lymphocytes (TILs) in breast cancer: recommendations by an international TILs-working group 2014 Ann Oncol mdu450 first published online 11 September 2014 https://doi.org/10.1093/annonc/mdu450. By permission of Oxford University Press on behalf of the European Society for Medical Oncology.

Figure 2

Canine transmissible venereal tumor, vagina, hematoxylin and eosin 40×: sheet of neoplastic round cells, characterized by a moderate amount of lightly eosinophilic cytoplasm, intermediate nucleus-cytoplasmic ratio, and a round nucleus with prominent nucleolus. Intermingled with neoplastic cells are numerous tumor infiltrating lymphocytes.

Figure 3

(A,B) Canine mammary comedocarcinoma histological grade III, hematoxylin and eosin. (A) The tumoral stromal area is massively effaced by tumor infiltrating lymphocytes (TILs), 10×; (B) higher power magnification showing mainly lymphocytes and plasma cells among TILs, 20×. (C,D) Feline mammary simple tubular carcinoma, histological grade II, hematoxylin and eosin. The stromal area is strongly infiltrated by TILs, 10×; higher magnification depicting mainly small lymphocytes among TILs.

Figure 4

Comparative similarities of TIL evaluation in human and companion animal breast cancer. Several similarities exist between species, including immune checkpoint expression of TILs; however, further evidence is required in companion animals to elucidate the role of TILs as a biomarker for response to immunotherapy. Neoadjuvant chemotherapy and TILs as a marker for therapeutic response also require further study in companion animals.

Figure 5

Canine cutaneous histiocytoma, hematoxylin, and eosin: (A) the dermis is expanded by a dome-shaped densely cellular neoplasm, characterized at the base by a densely basophilic area suggestive of lymphocyte infiltration. (B) The neoplasm is composed of round histiocytic cells to which numerous lymphocytes are mixed, that are responsible for tumor regression, 20×.

Figure 6

Canine urothelial cell carcinoma, hematoxylin, and eosin, urothelial cell carcinoma. (A) Moderate numbers of lymphocytes are multifocally present within the fibrovascular stroma adjacent to the neoplastic proliferative front, 4×. (B) Focally extensive increase in numbers of plasma cells (tumor infiltrating plasma cells, TIPs) surround cancer nests, 20×.

Figure 7

Canine pulmonary carcinoma (with metastasis to right bronchial lymph node) classified as grade III, hematoxylin, and eosin. (A) High-grade TILs: numerous lymphocytes are distributed adjacent to the cancer nests, 10×. (B) Higher magnification, 20×.