Natural Killer and T Cell Infiltration in Canine Osteosarcoma: Clinical Implications and Translational Relevance

Abstract

Metastatic osteosarcoma has a bleak prognosis in both humans and dogs, and there have been minimal therapeutic advances in recent decades to improve outcomes. Naturally occurring osteosarcoma in dogs is shown to be a highly suitable model for human osteosarcoma, and limited data suggest the similarities between species extend into immune responses to cancer. Studies show that immune infiltrates in canine osteosarcoma resemble those of human osteosarcoma, and the analysis of tumor immune constituents as predictors of therapeutic response is a promising direction for future research. Additionally, clinical studies in dogs have piloted the use of NK transfer to treat osteosarcoma and can serve as valuable precursors to clinical trials in humans. Cytotoxic lymphocytes in dogs and humans with osteosarcoma have increased activation and exhaustion markers within tumors compared with blood. Accordingly, NK and T cells have complex interactions among cancer cells and other immune cells, which can lead to changes in pathways that work both for and against the tumor. Studies focused on NK and T cell interactions within the tumor microenvironment can open the door to targeted therapies, such as checkpoint inhibitors. Specifically, PD-1/PD-L1 checkpoint expression is conserved across tumors in both species, but further characterization of PD-L1 in canine osteosarcoma is needed to assess its prognostic significance compared with humans. Ultimately, a comparative understanding of T and NK cells in the osteosarcoma tumor microenvironment in both dogs and humans can be a platform for translational studies that improve outcomes in both dogs and humans with this frequently aggressive disease.

Advancements in osteosarcoma management: integrating immune microenvironment insights with immunotherapeutic strategies

“…Specifically, NK cell-mediated IFN-γ release plays a crucial role in the activation of CD4 + T cells and is vital for the proliferation of CD8 + T-cell precursors ( Myers and Miller, 2021 ). Preclinical investigations have shown the capability of NK cells to efficiently eliminate osteosarcoma cells ( Razmara et al, 2021 ).…”

Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment

“… 258 Canine osteosarcomas are the only other spontaneous osteosarcomas in large animals, and their immune infiltrates resemble those of human osteosarcomas. 90 It should be noted that mifamurtide (MTP-PE), the most effective systemic agent in canine osteosarcoma, has been approved in Europe and Japan for clinical use. 90 Another example, DXS31-164, a Listeria monocytogenes vaccine (recombinant Listeria monocytogenes expressing a chimeric human HER2/neu construct), effectively triggers a HER2/neu-specific immune response to suppress pulmonary metastasis and prolong overall survival in a canine osteosarcoma model.…”

“… 90 It should be noted that mifamurtide (MTP-PE), the most effective systemic agent in canine osteosarcoma, has been approved in Europe and Japan for clinical use. 90 Another example, DXS31-164, a Listeria monocytogenes vaccine (recombinant Listeria monocytogenes expressing a chimeric human HER2/neu construct), effectively triggers a HER2/neu-specific immune response to suppress pulmonary metastasis and prolong overall survival in a canine osteosarcoma model. 259 The study also suggested the excellent effects of DXS31-164 in the treatment of HER2/neu-positive osteosarcoma patients.…”

“…88 Osteosarcoma cells have been shown to be readily eliminated by NK cells in some preclinical studies. 89,90 For example, cultivation of NKs from normal donors with osteosarcoma feeder cells for one week resulted in a median killing effect of approximately 46.1%. 91,92 Notably, this cytotoxicity was not associated with the expression levels of NK receptor ligands but was significantly suppressed through the exposure of NKs to anti-DNAM-1 and anti-NKG2D antibodies.…”