Publicação
Serum levels and tumor expression of TIM-3 as a promising clinical biomarker in cats with mammary carcinoma
| Resumo: | T-cell Immunoglobulin and Mucin-domain containing molecule-3 (TIM-3) is an inhibitory receptor with a key role in regulating inflammation, autoimmunity and cancer progression. Recently, in order to overcome resistance to current immune checkpoint blockade therapies, TIM-3 has emerged as a promising targeting molecule for cancer immunotherapy. Although feline mammary carcinoma (FMC) is a valuable cancer model, no studies on the TIM-3 receptor have been developed in this species. Thus, in this study, 48 cats with mammary carcinoma were evaluated. Firstly, immunohistochemistry was performed to assess the TIM-3 expression in total (t), stromal (s) and intratumoral (i) tumor-infiltrating lymphocytes (TILs) and in cancer cells. In parallel, serum TIM-3 levels were quantified and compared with healthy controls using enzyme-linked immunosorbent assay (ELISA). Finally, the TIM-3 gene was sequenced from 19 tumor tissue samples to identify putative mutations. In FMC, our results demonstrated that sTILs-TIM3+ are more frequent than iTILs-TIM-3+, which are more abundant in luminal A/B subtypes. A positive correlation between sTILs-TIM-3+ and cancer cells-TIM-3+ and higher tumor malignancy grade was found (p=0.044 and p=0.018, respectively), whereas higher iTILs-TIM-3+ densities were mostly associated with a benign tumoral behavior. Additionally, higher densities of cancer cells overexpressing TIM-3 were associated with lymph node metastasis (p=0.025) and triple negative basal-like (p=0.038) and luminal B carcinomas (p=0.010), in contrast with luminal A mammary carcinomas. Finally, higher tTILs-TIM-3+ densities were predominantly associated with more favourable clinicopathological features, namely the percentage of tTILs-TIM-3+ was negatively associated with tumor metastasis (p=0.010) and tumor recurrence (p=0.013). Moreover, the TIM-3 serum levels were lower in the cats with mammary carcinoma than in the healthy group (p<0.001), being positively associated with higher densities of tTILs-TIM-3+ (p=0.016) and sTILs-TIM-3+ (p=0.023). From sequence analysis, only one mutation was identified in one tumor sample (intron 2: NC_058368.1: g.190379339 G>A). Altogether, in line with previous findings in human reports, our results suggest that the expression of TIM-3 among TILs subpopulations and cancer cells may differently influence the clinical outcome of cats with mammary carcinoma, reinforcing the hypothesis that feline mammary carcinoma is a valuable cancer model |
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| Autores principais: | Valente, Sofia Seixas Morais |
| Assunto: | Feline mammary carcinoma TIM-3 Tumor infiltrating lymphocytes Tumor microenvironment Immunotherapy Carcinoma mamário felino TIM-3 Linfócitos infiltrantes do tumor Microambiente tumoral Imunoterapia |
| Ano: | 2023 |
| País: | Portugal |
| Tipo de documento: | dissertação de mestrado |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | T-cell Immunoglobulin and Mucin-domain containing molecule-3 (TIM-3) is an inhibitory receptor with a key role in regulating inflammation, autoimmunity and cancer progression. Recently, in order to overcome resistance to current immune checkpoint blockade therapies, TIM-3 has emerged as a promising targeting molecule for cancer immunotherapy. Although feline mammary carcinoma (FMC) is a valuable cancer model, no studies on the TIM-3 receptor have been developed in this species. Thus, in this study, 48 cats with mammary carcinoma were evaluated. Firstly, immunohistochemistry was performed to assess the TIM-3 expression in total (t), stromal (s) and intratumoral (i) tumor-infiltrating lymphocytes (TILs) and in cancer cells. In parallel, serum TIM-3 levels were quantified and compared with healthy controls using enzyme-linked immunosorbent assay (ELISA). Finally, the TIM-3 gene was sequenced from 19 tumor tissue samples to identify putative mutations. In FMC, our results demonstrated that sTILs-TIM3+ are more frequent than iTILs-TIM-3+, which are more abundant in luminal A/B subtypes. A positive correlation between sTILs-TIM-3+ and cancer cells-TIM-3+ and higher tumor malignancy grade was found (p=0.044 and p=0.018, respectively), whereas higher iTILs-TIM-3+ densities were mostly associated with a benign tumoral behavior. Additionally, higher densities of cancer cells overexpressing TIM-3 were associated with lymph node metastasis (p=0.025) and triple negative basal-like (p=0.038) and luminal B carcinomas (p=0.010), in contrast with luminal A mammary carcinomas. Finally, higher tTILs-TIM-3+ densities were predominantly associated with more favourable clinicopathological features, namely the percentage of tTILs-TIM-3+ was negatively associated with tumor metastasis (p=0.010) and tumor recurrence (p=0.013). Moreover, the TIM-3 serum levels were lower in the cats with mammary carcinoma than in the healthy group (p<0.001), being positively associated with higher densities of tTILs-TIM-3+ (p=0.016) and sTILs-TIM-3+ (p=0.023). From sequence analysis, only one mutation was identified in one tumor sample (intron 2: NC_058368.1: g.190379339 G>A). Altogether, in line with previous findings in human reports, our results suggest that the expression of TIM-3 among TILs subpopulations and cancer cells may differently influence the clinical outcome of cats with mammary carcinoma, reinforcing the hypothesis that feline mammary carcinoma is a valuable cancer model |
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