Interação entre hospedeiro e tumor venéreo transmissível canino: diversidade de células mononucleares e do complexo principal de histocompatibilidade
Carregando...
Data
2017-08-01
Autores
Duzanski, Anderson do Prado [UNESP]
Título da Revista
ISSN da Revista
Título de Volume
Editor
Universidade Estadual Paulista (Unesp)
Resumo
O tumor venéreo transmissível canino (TVTC) ocorre naturalmente em cães, sem predileção por raça ou sexo sendo transmitido durante o coito ou hábitos sociais. É também um tumor transplantável experimentalmente e tem sido utilizado como modelo para o estudo da relação entre tumor e hospedeiro. Apesar da maior infiltração inflamatória intratumoral e da expressão de moléculas do complexo principal de histocompatibilidade (MHC) estar associada à regressão do tumor, o papel central das células imunes do hospedeiro na evolução clínica do TVTC ainda não está claro. Neste estudo nós buscamos analisar a interação entre TVTC natural e hospedeiro, especialmente sob o ponto de vista da imunidade celular tumoral. Aqui nós identificamos e quantificamos por citometria de fluxo células T (CD3+, CD4+ e CD8+), células NK, células B, macrófagos, em amostras de sangue e de tumor, além da expressão imunoistoquímica de moléculas do MHC de classe I e II, sobretudo nas diferentes fases clínicas do tumor, assim como classificamos os subtipos citológicos do tumor e avaliamos o comportamento tumoral frente ao tratamento quimioterápico com sulfato de vincristina em uma amostra de 22 cães com TVTC natural. A quimioterapia foi efetiva no tratamento da maioria dos casos. Encontramos predomínio de TVTC linfocitóide e que metástases e resistência quimioterápica ocorreram apenas nos tumores de fenótipo linfocitóide e misto. Identificamos aumento significativo na expressão de moléculas de MHC classe I e II na fase de regressão. As células T CD3+ estavam igualmente presentes nas fases de progressão e regressão. Porém, as células T (CD4+ e CD8+), células NK e macrófagos estavam mais presentes na fase de regressão, enquanto as células B estavam em maior quantidade na fase de progressão, mas não foi possível correlacionar a fase clínica do tumor com um único tipo predominante de infiltrado inflamatório intratumoral. Ainda, a fase clínica e o subtipo citológico do tumor natural não pareceram ser determinantes na resposta ao tratamento quimioterápico, assim como não encontramos diferença imune expressiva entre os subtipos citológicos do tumor, indicando, portanto, não haver diferença quanto à interação tumor/hospedeiro. Nossos achados em citometria de fluxo mostram que a maior presença de células T no microambiente tumoral antes do início da quimioterapia não favoreceu a regressão do tumor, ao contrário da população macrofágica que parece ter contribuído para o menor número de sessões quimioterápicas. Identificamos ainda que cães fêmeas e cães de raça, em geral, apresentaram maior presença de células mononucleares circulantes e infiltrantes, e que as fêmeas mostraram evidência de resposta mais favorável à remissão completa do tumor acompanhada de quimioterapia em comparação aos cães machos, uma vez que as fêmeas apresentaram maior infiltrado intratumoral de macrófagos. Por fim, nossos dados não sustentam uma forte evidência de regressão espontânea no TVTC natural. Mais estudos são necessários para melhor entender os mecanismos da interação entre células do tumor e hospedeiras e a sua implicação na imunidade antitumoral, uma vez que, na ausência de tratamento o tumor natural provavelmente não regride espontaneamente, pois o sistema imune do cão parece ser requisitado pelo tumor durante os eventos biológicos associados à tumorigênese e ao escape da imunovigilância.
The transmissible venereal canine tumor (CTVT) occurs naturally in dogs, without predilection for race or gender being transmitted during intercourse or social habits. It is also an experimentally transplantable tumor and it has been used as a pattern for the study about the relationship between the tumor and the host. Despite the greater intratumoral inflammatory infiltration and the expression of major histocompatibility complex molecules (MHC) is associated with tumor regression, the central role of host immune cells in the CTVT clinical evolution is not clear yet. In this study we sought to analyze the interaction between natural and host CTVT, especially from the point of view of tumor cell immunity. Here we identify and quantify by flow cytometry cells T (CD3+, CD4+ e CD8+), cells NK, cells B, macrophages, in blood and tumor samples, besides the immune histochemical expression of MHC class I and II molecules, specially in the different clinical phases of the tumor as well as classifying the cytological subtypes of the tumor and evaluating the tumor behavior against the chemotherapy treatment with vincristine sulfate in a sample of 22 dogs with natural CTVT. Chemotherapy was effective in the treatment of most cases. We found a predominance of lymphocytoid CTVT and that metastases and chemotherapeutic resistance occurred only in tumors of lymphocytoid and mixed phenotype. We identified a significant increase in the expression of MHC class I and II molecules in the regression phase. T CD3+ cells were also present in the progression and regression phases. However, T cells (CD4 + and CD8 +), NK cells and macrophages were more present in the regression phase, while B cells were more in the progression phase, but it was not possible to correlate the clinical phase of the tumor with a single type prevalent of infiltrated intratumoral inflammatory. Moreover, the clinical and cytologic subtype of the natural tumor did not appear to be determinant in the response to the chemotherapeutic treatment, nor did we find an expressive immune difference between the cytological subtypes of the tumor, indicating, therefore, that there was no difference in the tumor/host interaction. Our findings in flow cytometry show that the increased presence of T cells in the tumor microenvironment prior to the initiation of chemotherapy did not favor tumor regression, unlike the macrophagic population that appears to have contributed to the lower number of chemotherapy sessions. We also identified that female dogs and breed dogs in general had a higher presence of circulating and infiltrating mononuclear cells and that females showed evidence of a more favorable response to complete remission of the tumor accompanied by chemotherapy compared to male dogs, since females showed greater intratumoral infiltration of macrophages. Finally, our data do not support strong evidence of spontaneous regression in natural CTVT. More studies are necessary to better understand the mechanisms of interaction between tumor cells and hosts and their implication in antitumor immunity, since in the absence of treatment the natural tumor probably does not regress spontaneously, as the dog's immune system appears to be required by the tumor during the biological events associated with tumorigenesis and the escape of immunovigilance.
The transmissible venereal canine tumor (CTVT) occurs naturally in dogs, without predilection for race or gender being transmitted during intercourse or social habits. It is also an experimentally transplantable tumor and it has been used as a pattern for the study about the relationship between the tumor and the host. Despite the greater intratumoral inflammatory infiltration and the expression of major histocompatibility complex molecules (MHC) is associated with tumor regression, the central role of host immune cells in the CTVT clinical evolution is not clear yet. In this study we sought to analyze the interaction between natural and host CTVT, especially from the point of view of tumor cell immunity. Here we identify and quantify by flow cytometry cells T (CD3+, CD4+ e CD8+), cells NK, cells B, macrophages, in blood and tumor samples, besides the immune histochemical expression of MHC class I and II molecules, specially in the different clinical phases of the tumor as well as classifying the cytological subtypes of the tumor and evaluating the tumor behavior against the chemotherapy treatment with vincristine sulfate in a sample of 22 dogs with natural CTVT. Chemotherapy was effective in the treatment of most cases. We found a predominance of lymphocytoid CTVT and that metastases and chemotherapeutic resistance occurred only in tumors of lymphocytoid and mixed phenotype. We identified a significant increase in the expression of MHC class I and II molecules in the regression phase. T CD3+ cells were also present in the progression and regression phases. However, T cells (CD4 + and CD8 +), NK cells and macrophages were more present in the regression phase, while B cells were more in the progression phase, but it was not possible to correlate the clinical phase of the tumor with a single type prevalent of infiltrated intratumoral inflammatory. Moreover, the clinical and cytologic subtype of the natural tumor did not appear to be determinant in the response to the chemotherapeutic treatment, nor did we find an expressive immune difference between the cytological subtypes of the tumor, indicating, therefore, that there was no difference in the tumor/host interaction. Our findings in flow cytometry show that the increased presence of T cells in the tumor microenvironment prior to the initiation of chemotherapy did not favor tumor regression, unlike the macrophagic population that appears to have contributed to the lower number of chemotherapy sessions. We also identified that female dogs and breed dogs in general had a higher presence of circulating and infiltrating mononuclear cells and that females showed evidence of a more favorable response to complete remission of the tumor accompanied by chemotherapy compared to male dogs, since females showed greater intratumoral infiltration of macrophages. Finally, our data do not support strong evidence of spontaneous regression in natural CTVT. More studies are necessary to better understand the mechanisms of interaction between tumor cells and hosts and their implication in antitumor immunity, since in the absence of treatment the natural tumor probably does not regress spontaneously, as the dog's immune system appears to be required by the tumor during the biological events associated with tumorigenesis and the escape of immunovigilance.
Descrição
Palavras-chave
Cão, TVTC, Imunidade celular tumoral, MHC classe I e II, Vincristina, Dog, CTVT, Tumor cell immunity, MHC class I e II, Vincristine