Publicação
Characterization of immune responses in feline mammary carcinoma towards the development of improved diagnostic tools and molecular therapies
| Resumo: | Feline mammary carcinoma (FMC) is one of the most common tumors in female cats, being highly malignant and leading to early metastasis. In most of the cases the diagnosis is late and often leads to mastectomy to prevent the formation of new tumors in the remaining mammary glands. Thus, the development of new diagnostic and prognostic tools and molecular therapies are crucial to improve the efficient detection and treatment of these animals. In this study, the main goals were to characterize distinct immune cell subpopulations in the tumor microenvironment (TME) of FMC and to evaluate the PD-1/PDL1 and the VEGF-A/VEGFRs pathways in serum and tissue samples of cats with mammary carcinoma, in order to suggest new diagnostic and prognostic biomarkers and novel therapies for FMC. Results showed that cats with mammary carcinoma with higher densities of stromal CD8+ tumor infiltrating lymphocytes (TILs) had longer disease-free survival and overall survival, suggesting its usefulness as a favorable and novel prognostic biomarker for FMC. Furthermore, and according to the molecular subtype, triple negative (TN) normal-like tumors showed higher densities of stromal CD3+, CD8+ and CD68+ immune cells, and lower expression of PD-L1 in TILs and cancer cells, compared to HER2-positive tumor subtype. These results suggest that HER2-positive tumors had a highly immunosuppressive TME. Additionally, results demonstrated that cats with HER2-positive and TN normal-like molecular subtypes showed higher serum PD-1, PD-L1, VEGF-A, VEGFR-1, VEGFR-2 levels than healthy controls, suggesting that these molecules might be potential biomarkers for the diagnosis of cats with these two aggressive molecular subtypes. Results also suggest that these animals were under systemic immunosuppression, and may benefit from anti-PD- 1/PD-L1 immunotherapies or anti-angiogenic agents. In sum, these results identified a novel prognostic factor for FMC, and new molecules that may serve as promising non-invasive diagnostic biomarkers for cats with HER2-positive and TN normal-like molecular subtypes. Moreover, this project may lead to the development of new drugs, in order to improve the treatment of cats with mammary carcinoma. Additionally, the data obtained support the idea that spontaneous FMC is a suitable cancer model for the study of human breast cancer. |
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| Autores principais: | Nascimento, Ana Catarina Gaspar do |
| Assunto: | Feline mammary carcinoma Tumor microenvironment Tumor infiltrating lymphocytes PD-1/PD-L1 axis Angiogenesis Carcinoma mamário felino Microambiente tumoral Linfócitos infiltrantes tumorais Eixo PD-1/PD-L1 Angiogénese |
| Ano: | 2022 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Feline mammary carcinoma (FMC) is one of the most common tumors in female cats, being highly malignant and leading to early metastasis. In most of the cases the diagnosis is late and often leads to mastectomy to prevent the formation of new tumors in the remaining mammary glands. Thus, the development of new diagnostic and prognostic tools and molecular therapies are crucial to improve the efficient detection and treatment of these animals. In this study, the main goals were to characterize distinct immune cell subpopulations in the tumor microenvironment (TME) of FMC and to evaluate the PD-1/PDL1 and the VEGF-A/VEGFRs pathways in serum and tissue samples of cats with mammary carcinoma, in order to suggest new diagnostic and prognostic biomarkers and novel therapies for FMC. Results showed that cats with mammary carcinoma with higher densities of stromal CD8+ tumor infiltrating lymphocytes (TILs) had longer disease-free survival and overall survival, suggesting its usefulness as a favorable and novel prognostic biomarker for FMC. Furthermore, and according to the molecular subtype, triple negative (TN) normal-like tumors showed higher densities of stromal CD3+, CD8+ and CD68+ immune cells, and lower expression of PD-L1 in TILs and cancer cells, compared to HER2-positive tumor subtype. These results suggest that HER2-positive tumors had a highly immunosuppressive TME. Additionally, results demonstrated that cats with HER2-positive and TN normal-like molecular subtypes showed higher serum PD-1, PD-L1, VEGF-A, VEGFR-1, VEGFR-2 levels than healthy controls, suggesting that these molecules might be potential biomarkers for the diagnosis of cats with these two aggressive molecular subtypes. Results also suggest that these animals were under systemic immunosuppression, and may benefit from anti-PD- 1/PD-L1 immunotherapies or anti-angiogenic agents. In sum, these results identified a novel prognostic factor for FMC, and new molecules that may serve as promising non-invasive diagnostic biomarkers for cats with HER2-positive and TN normal-like molecular subtypes. Moreover, this project may lead to the development of new drugs, in order to improve the treatment of cats with mammary carcinoma. Additionally, the data obtained support the idea that spontaneous FMC is a suitable cancer model for the study of human breast cancer. |
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