Prostate cancer is among the most common malignancies in males in the United States and adenocarcinoma accounts for 95% of all malignancies of prostate. Rarely prostate cancer can also present as small cell carcinoma. Pure small cell carcinoma is rare at time of initial diagnosis (<2%) however neuroendocrine differentiation into small cell carcinoma may emerge in men who have had previous treatment with ADT for prostate adenocarcinoma. These tumors, sometimes called treatment-related neuroendocrine prostate cancers or aggressive-variant prostate cancers, are increasingly recognized in the castration-resistant phases of disease progression. They account for less than 1% of all prostate cancers. A 73-year-old otherwise male had routine health screening in May 2018. Prostate specific antigen (PSA) level was elevated at 9.53 ng/mL. He had not had a screening PSA for at least two prior years but this was a significant change from prior levels. Patient was asymptomatic however the abnormal laboratory evaluation prompted consultation with Urology. Biopsy of prostate gland confirmed prostatic adenocarcinoma with Gleason's score of 5+ 4 = 9 with bilateral gland involvement. Imaging studies including CT scan of abdomen and pelvis, a bone scan and a PET scan showed no clear evidence of metastatic disease. Patient's clinical stage was determined to be IIIC with T2c N0 M0 disease. Patient began treatment with androgen deprivation therapy and received definitive radiation treatment with external bean radiation therapy from July to September 2018. PSA was 0.08 ng/ml at the end of radiation treatment. Patient did well for about 15 months, after which he had multiple hospital admissions for dyspnea, fluid retention and lower extremity edema. He was also found to have refractory hypokalemia. Patient underwent MRI brain which revealed numerous small enhancing calvarial and skull base lesions consistent with bony metastasis in the skull. Patient also underwent PET/CT scan which showed numerous thoracic spine bony lesions, numerous to count bony metastasis throughout the lumbar spine and pelvis, as well as multiple hepatic lesions. Patient underwent biopsy of right hepatic lobe lesion and pathology was consistent with small cell carcinoma with positive neuroendocrine markers including CD56, synaptophysin and TTF-1. Interestingly patient’s PSA was only 0.09ng/dL. Given refractory hypokalemia, paraneoplastic syndrome was suspected and further work-up was initiated. Serum cortisol levels were elevated at 119.6 mcg/dL (3.7-19.4) and ACTH level was 333 pg/mL (7.2 - 63.3). Aldosterone level was <1 ng/dL (0 - 30.0). Patient was diagnosed with paraneoplastic Cushing syndrome. Given aggressive nature of this small cell transformation, patient was started on treatment with systemic chemotherapy with Carboplatin/Etoposide during the hospital stay, with stabilization of potassium levels. Prostate small cell carcinoma poses a challenge for diagnosis and treatment. In contrast to adenocarcinoma of the prostate, serum prostate-specific antigen (PSA) is not predictive of disease severity, nor is it a useful tumor marker for monitoring progression or surveillance. Patients with prostate small cell cancer presents with more diverse symptoms than any other prostate cancer since it tends to metastasize early. Also paraneoplastic syndromes are more common in prostate small cell cancers as well.

Autoimmune hemolytic anemia (AIHA) is a disease process that involves the destruction of red blood cells mediated by the humoral immune system. It can be characterized as a cold agglutinin syndrome, paroxysmal cold hemoglobinuria, and warm, mixed type, and drug-induced AIHA. Although a well-established relationship exists between the presence of AIHA and lymphoproliferative malignancy, AIHA rarely presents in association with solid malignancies. An analysis of the limited number of published cases of AIHA in association with solid malignancies performed showed that AIHA may present before the diagnosis of a solid malignancy, concurrently with the presence of a solid malignancy, or even on resolution of a solid malignancy. Few cases of solid cancers associated with AIHA have been reported. AIHA rarely presents as a paraneoplastic syndrome indicating existence of a solid cancer. We report a case of inflammatory breast cancer with AIHA.

A síndrome paraneoplásica é definida como um conjunto de sinais e sintomas que acontecem distantes do tumor primário e de suas metástases. Nos mastocitomas, os sinais sistêmicos mais comuns são os sinais gastrintestinais secundários à liberação de histamina, heparina e outras substâncias bioativas contidas no interior dos mastócitos neoplásicos. Em decorrência da ação sistêmica destas substâncias, a ulceração gastrintestinal é a principal síndrome paraneoplásica descrita. Assim, o presente trabalho avalia a ocorrência de lesões gastroduodenais em cães com mastocitoma cutâneo no momento do diagnóstico, correlacionando seu aparecimento com a apresentação clínica da doença, aparência macroscópica do tumor, diferentes marcadores prognósticos pré-estabelecidos pela literatura e valores plasmáticos de histamina. Para tal, foram utilizados 41 cães da rotina clinico/oncológica do Hospital de Clínicas Veterinárias da Universidade Federal do Rio Grande do Sul (HCV-UFRGS) com diagnóstico confirmado de mastocitoma cutâneo. Os animais foram avaliados clinicamente e, posteriormente, foram submetidos à cirurgia para exérese do tumor e exame endoscópico para avaliação do esôfago, estômago e porção proximal do duodeno. Todos os cães foram avaliados quanto a presença e a gravidade dos sinais clínicos, velocidade de crescimento tumoral, número e localização dos nódulos, tamanho tumoral, características macroscópicas do tumor, presença de metástase em linfonodo regional, classificação histopatológica, índice mitótico e valor de histamina plasmática, buscando-se estabelecer uma relação com o surgimento e a gravidade das lesões gástricas e duodenais. A análise macro e microscópica da mucosa gástrica e duodenal, não evidenciou lesões compatíveis com úlceração grave em nenhum dos cães avaliados. A ocorrência de sinais clínicos gastrintestinais foi observada em 41,5% dos casos e padrões inflamatórios, sugestivos de gastrite, foram evidenciados tanto no exame endoscópico quanto no exame histopatológico. Sendo assim, na população estudada, as lesões gastroduodenais observadas foram consideradas leves no momento do diagnóstico e não apresentaram relação estatística com as variáveis estudadas, sugerindo que a heterogenicidade da população possa ter contribuído para os resultados, ou ainda que outros fatores possam influenciar a degranulação dos mastócitos neoplásicos. / Paraneoplastic syndrome is defined as a set of signs and symptoms that are not related to the local effect of the primary tumor or its metastases. Gastrointestinal ulceration is the most common sign attributed to mast cell tumor’s paraneoplastic syndrome in dogs. In mastocytoma, release of histamine, heparin, and other bioactive substances by the neoplastic mast cells can lead to increased systemic action of these substances and induce gastrointestinal disturbances. This study aimed to evaluate the occurrence of gastroduodenal lesions in dogs with cutaneous mast cell tumor at the time of diagnosis and correlate them to the clinical presentation of the disease, tumor’s macroscopic aspects, neoplasic prognostic markers, and plasmatic histamine values. We evaluated 41 dogs with cutaneous mast cell tumor diagnosed at the oncology service of the Veterinary Hospital of the Federal University of Rio Grande do Sul (UFRGS-HCV). After clinical examination, as the animals underwent surgery to remove the tumor and endoscopy to evaluate the esophagus, stomach and proximal duodenum was performed Presence and severity of clinical signs, neoplasms macroscopic characteristics, tumor size, number and location of neoplasic masses, tumor growth rate, presence of regional lymph node metastasis, histopathological classification, mitotic index, and plasmatic histamine concentration were determined and correlated with gastrodueodenal endoscopic findings. The macro and microscopic analyses of the gastric and duodenal mucosa showed no lesions compatible with ulceration in any of the pacients. The occurrence of gastrointestinal clinical signs was observed in 41.5% of cases and inflammatory patterns, suggestive of gastritis were evidenced in both endoscopic and histopathological examination; however, its correlation with the presence of mast cell tumor could not be established. Therefore, in this population, gastroduodenal lesions observed were considered mild at diagnosis and had no relation with the variables analyzed, suggesting that the heterogeneity of the population may have contributed to the results or that other factors may influence the degranulation of mast cells neoplastic.

A síndrome paraneoplásica é definida como um conjunto de sinais e sintomas que acontecem distantes do tumor primário e de suas metástases. Nos mastocitomas, os sinais sistêmicos mais comuns são os sinais gastrintestinais secundários à liberação de histamina, heparina e outras substâncias bioativas contidas no interior dos mastócitos neoplásicos. Em decorrência da ação sistêmica destas substâncias, a ulceração gastrintestinal é a principal síndrome paraneoplásica descrita. Assim, o presente trabalho avalia a ocorrência de lesões gastroduodenais em cães com mastocitoma cutâneo no momento do diagnóstico, correlacionando seu aparecimento com a apresentação clínica da doença, aparência macroscópica do tumor, diferentes marcadores prognósticos pré-estabelecidos pela literatura e valores plasmáticos de histamina. Para tal, foram utilizados 41 cães da rotina clinico/oncológica do Hospital de Clínicas Veterinárias da Universidade Federal do Rio Grande do Sul (HCV-UFRGS) com diagnóstico confirmado de mastocitoma cutâneo. Os animais foram avaliados clinicamente e, posteriormente, foram submetidos à cirurgia para exérese do tumor e exame endoscópico para avaliação do esôfago, estômago e porção proximal do duodeno. Todos os cães foram avaliados quanto a presença e a gravidade dos sinais clínicos, velocidade de crescimento tumoral, número e localização dos nódulos, tamanho tumoral, características macroscópicas do tumor, presença de metástase em linfonodo regional, classificação histopatológica, índice mitótico e valor de histamina plasmática, buscando-se estabelecer uma relação com o surgimento e a gravidade das lesões gástricas e duodenais. A análise macro e microscópica da mucosa gástrica e duodenal, não evidenciou lesões compatíveis com úlceração grave em nenhum dos cães avaliados. A ocorrência de sinais clínicos gastrintestinais foi observada em 41,5% dos casos e padrões inflamatórios, sugestivos de gastrite, foram evidenciados tanto no exame endoscópico quanto no exame histopatológico. Sendo assim, na população estudada, as lesões gastroduodenais observadas foram consideradas leves no momento do diagnóstico e não apresentaram relação estatística com as variáveis estudadas, sugerindo que a heterogenicidade da população possa ter contribuído para os resultados, ou ainda que outros fatores possam influenciar a degranulação dos mastócitos neoplásicos. / Paraneoplastic syndrome is defined as a set of signs and symptoms that are not related to the local effect of the primary tumor or its metastases. Gastrointestinal ulceration is the most common sign attributed to mast cell tumor’s paraneoplastic syndrome in dogs. In mastocytoma, release of histamine, heparin, and other bioactive substances by the neoplastic mast cells can lead to increased systemic action of these substances and induce gastrointestinal disturbances. This study aimed to evaluate the occurrence of gastroduodenal lesions in dogs with cutaneous mast cell tumor at the time of diagnosis and correlate them to the clinical presentation of the disease, tumor’s macroscopic aspects, neoplasic prognostic markers, and plasmatic histamine values. We evaluated 41 dogs with cutaneous mast cell tumor diagnosed at the oncology service of the Veterinary Hospital of the Federal University of Rio Grande do Sul (UFRGS-HCV). After clinical examination, as the animals underwent surgery to remove the tumor and endoscopy to evaluate the esophagus, stomach and proximal duodenum was performed Presence and severity of clinical signs, neoplasms macroscopic characteristics, tumor size, number and location of neoplasic masses, tumor growth rate, presence of regional lymph node metastasis, histopathological classification, mitotic index, and plasmatic histamine concentration were determined and correlated with gastrodueodenal endoscopic findings. The macro and microscopic analyses of the gastric and duodenal mucosa showed no lesions compatible with ulceration in any of the pacients. The occurrence of gastrointestinal clinical signs was observed in 41.5% of cases and inflammatory patterns, suggestive of gastritis were evidenced in both endoscopic and histopathological examination; however, its correlation with the presence of mast cell tumor could not be established. Therefore, in this population, gastroduodenal lesions observed were considered mild at diagnosis and had no relation with the variables analyzed, suggesting that the heterogeneity of the population may have contributed to the results or that other factors may influence the degranulation of mast cells neoplastic.

A síndrome paraneoplásica é definida como um conjunto de sinais e sintomas que acontecem distantes do tumor primário e de suas metástases. Nos mastocitomas, os sinais sistêmicos mais comuns são os sinais gastrintestinais secundários à liberação de histamina, heparina e outras substâncias bioativas contidas no interior dos mastócitos neoplásicos. Em decorrência da ação sistêmica destas substâncias, a ulceração gastrintestinal é a principal síndrome paraneoplásica descrita. Assim, o presente trabalho avalia a ocorrência de lesões gastroduodenais em cães com mastocitoma cutâneo no momento do diagnóstico, correlacionando seu aparecimento com a apresentação clínica da doença, aparência macroscópica do tumor, diferentes marcadores prognósticos pré-estabelecidos pela literatura e valores plasmáticos de histamina. Para tal, foram utilizados 41 cães da rotina clinico/oncológica do Hospital de Clínicas Veterinárias da Universidade Federal do Rio Grande do Sul (HCV-UFRGS) com diagnóstico confirmado de mastocitoma cutâneo. Os animais foram avaliados clinicamente e, posteriormente, foram submetidos à cirurgia para exérese do tumor e exame endoscópico para avaliação do esôfago, estômago e porção proximal do duodeno. Todos os cães foram avaliados quanto a presença e a gravidade dos sinais clínicos, velocidade de crescimento tumoral, número e localização dos nódulos, tamanho tumoral, características macroscópicas do tumor, presença de metástase em linfonodo regional, classificação histopatológica, índice mitótico e valor de histamina plasmática, buscando-se estabelecer uma relação com o surgimento e a gravidade das lesões gástricas e duodenais. A análise macro e microscópica da mucosa gástrica e duodenal, não evidenciou lesões compatíveis com úlceração grave em nenhum dos cães avaliados. A ocorrência de sinais clínicos gastrintestinais foi observada em 41,5% dos casos e padrões inflamatórios, sugestivos de gastrite, foram evidenciados tanto no exame endoscópico quanto no exame histopatológico. Sendo assim, na população estudada, as lesões gastroduodenais observadas foram consideradas leves no momento do diagnóstico e não apresentaram relação estatística com as variáveis estudadas, sugerindo que a heterogenicidade da população possa ter contribuído para os resultados, ou ainda que outros fatores possam influenciar a degranulação dos mastócitos neoplásicos. / Paraneoplastic syndrome is defined as a set of signs and symptoms that are not related to the local effect of the primary tumor or its metastases. Gastrointestinal ulceration is the most common sign attributed to mast cell tumor’s paraneoplastic syndrome in dogs. In mastocytoma, release of histamine, heparin, and other bioactive substances by the neoplastic mast cells can lead to increased systemic action of these substances and induce gastrointestinal disturbances. This study aimed to evaluate the occurrence of gastroduodenal lesions in dogs with cutaneous mast cell tumor at the time of diagnosis and correlate them to the clinical presentation of the disease, tumor’s macroscopic aspects, neoplasic prognostic markers, and plasmatic histamine values. We evaluated 41 dogs with cutaneous mast cell tumor diagnosed at the oncology service of the Veterinary Hospital of the Federal University of Rio Grande do Sul (UFRGS-HCV). After clinical examination, as the animals underwent surgery to remove the tumor and endoscopy to evaluate the esophagus, stomach and proximal duodenum was performed Presence and severity of clinical signs, neoplasms macroscopic characteristics, tumor size, number and location of neoplasic masses, tumor growth rate, presence of regional lymph node metastasis, histopathological classification, mitotic index, and plasmatic histamine concentration were determined and correlated with gastrodueodenal endoscopic findings. The macro and microscopic analyses of the gastric and duodenal mucosa showed no lesions compatible with ulceration in any of the pacients. The occurrence of gastrointestinal clinical signs was observed in 41.5% of cases and inflammatory patterns, suggestive of gastritis were evidenced in both endoscopic and histopathological examination; however, its correlation with the presence of mast cell tumor could not be established. Therefore, in this population, gastroduodenal lesions observed were considered mild at diagnosis and had no relation with the variables analyzed, suggesting that the heterogeneity of the population may have contributed to the results or that other factors may influence the degranulation of mast cells neoplastic.

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No. of bitstreams: 2 Dissertação - Raquel Cunha Ribeiro - 2011.pdf: 1029530 bytes, checksum: 42ae98276f4f3f96f8d50c3bd9d72869 (MD5) license_rdf: 23148 bytes, checksum: 9da0b6dfac957114c6a7714714b86306 (MD5) Previous issue date: 2010-05-06 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES / Hypercalcemia is one of the most important and frequent signs of paraneoplastic syndrome in humans, however, the incidence of this abnormality is unknown in Veterinary Medicine. So, this study aimed to carry out clinical and pathological evaluations and verify the occurrence of hypercalcemia in female dogs with mammary gland cancer. Twenty animals were selected and allocated in two groups: A – eight animals in early stage (stage I); B – twelve animals in advanced stage (stage IV and V). First, the dog were submitted to routine physical examination and laboratory evaluation that included hemogram, total and ionized calcium, creatinine, albumin, phosphorus, parathyroid hormone, serum activity of alkaline phosphatase (ALP) and alanine aminotransferase (ALT). After, they were surgically treated and the removed tissue were sent for histologic evaluation. The data from clinical evaluation were analyzed using frequency tables and the comparison between the proportions of variables between groups were perfiemed by Fisher’s test (nonparametric) and within groups by Chi-square test (p<0,05). The frequency of mammary gland cancer was higher in uncastred female dogs with age between 10 and 12 years. Caudal abdominal and inguinal glands were the most affected. In relation to hypercalcemia frequency, there was not significant difference (p= 34,73%) among the groups by Fisher’s test. In group B, two dogs showed hypercalcemia and primary hyperparathyroidism was diagnosed in both animals. However, there was not significant difference in hypercalcemia frequency by Chi-square test (p<0,05%). Thus, it can be concluded that hypercalcemia associated with mammary gland cancer is an uncommon condition in female dogs. However, it is necessary more studies with larger number of animals for stablishment of a consistent correlation between the development of mammary cancer and hypercalcemia in female dogs. / A hipercalcemia maligna é uma das mais importantes e frequentes síndromes paraneoplásicas em pacientes humanos portadores de câncer, no entanto, a incidência dessas alterações ainda é desconhecida na Medicina Veterinária. Assim, objetivou-se com este estudo avaliar a ocorrência de hipercalcemia maligna em cadelas portadoras de diferentes tipos de câncer de mama, assim como associar estas alterações com o diagnóstico precoce (estágio clínico I) e tardio (estágio IV ou V) destas neoplasias. Para tal, utilizou-se 20 cadelas selecionadas a partir de exames clínico-laboratoriais e citologia aspirativa por agulha fina. As fêmeas caninas foram alocadas em dois grupos: Grupo A com oito animais em estágio inicial da doença (estadiamento clinico I) e Grupo B constituído de 12 cadelas em estágio avançado (estadiamento IV ou V). A avaliação clínico-laboratorial incluiu hemograma, dosagem de cálcio iônico e total, creatinina, albumina, fósforo, paratormônio, atividade sérica de fosfatase alcalina (ALP) e alanina amino-transferase. (ALT). Posteriormente, realizou-se tratamento cirúrgico e colheita de material para exame histopatológico. Os dados obtidos a partir da avaliação clínica foram analisados por meio de tabelas de frequência e a comparação entre as proporções das variáveis entre os grupos pelo teste não-paramétrico de Fisher e dentro dos grupos pelo teste de Qui-Quadrado (p<0,05). Observou-se maior frequencia do diagnóstico de tumor de mama em cadelas não castradas entre dez e 12 anos de idade, nas glândulas mamárias abdominais caudais e inguinais. Não houve diferença significativa (p=34,73%) ao comparar os grupos quanto à frequência de hipercalcemia, por meio do teste de Fisher. No grupo B, duas cadelas apresentaram hipercalcemia, sendo diagnosticado hiperparatireoidismo primário em ambas. No entanto, não houve diferença significativa na frequência de hipercalcemia, de acordo com o teste de Qui-quadrado (P<0,05%). Concluiu-se que a hipercalcemia associada ao câncer de mama é uma condição pouco frequente em fêmeas caninas. Contudo, sugere-se pesquisas científicas empregando-se um efetivo maior de animais a fim de correlacionar o desenvolvimento de câncer de mama e hipercalcemia maligna em fêmeas da espécie canina.

Les syndromes neurologiques paranéoplasiques (SNP) sont des maladies neurologiques rares, associés à une réponse immunitaire efficace contre un cancer sous-jacent exprimant un antigène également exprimé par des cellules du système nerveux central (SNC). Le cancer déclenche alors une réponse auto-immune secondaire qui provoque la destruction des cellules du SNC. Certains travaux récents suggèrent que l'immunité à médiation cellulaire associée à des auto-anticorps reconnaissant des antigènes intracellulaires pourrait jouer un rôle majeur, bien qu'encore mal compris, dans la physiopathologie des SNP. Les exemples de SNP les plus représentatifs sont le syndrome Hu, qui conduit à la perte de diverses populations de neurones du SNC et l'ataxie cérébelleuse subaiguë (PCD en anglais, pour Paraneoplastic Cerebellar Degeneration), caractérisée par la perte sélective des cellules de Purkinje du cervelet. Alors que le syndrome Hu se développe en général chez des patients présentant des tumeurs du poumon à petites cellules qui expriment l'antigène HuD spécifique des neurones, la majorité des patients souffrant de PCD présente un cancer gynécologique qui exprime la protéine CDR2, également exprimée dans les cellules de Purkinje. Afin de mieux cerner la physiopathologie des SNP et de tester l'implication de l'immunité cellulaire, notamment des lymphocytes T, nous avons durant ma thèse développé et analysé deux modèles murins, l'un pour le syndrome Hu et l'autre pour la PCD. Ces modèles reposent sur l'utilisation de souches de souris génétiquement modifiées : la souris CamK-HA, qui exprime l'hémagglutinine (HA) du virus de la grippe dans la plupart de ses neurones du SNC et la souris L7-HA dans laquelle la protéine HA est exprimée exclusivement par les cellules de Purkinje du cervelet. Dans ces souris, une réponse anti-tumorale est provoquée par l'injection de cellules tumorales 4T1 exprimant HA (4T1-HA). Afin le faciliter le suivi des réponses cellulaires contre l'antigène HA, nous avons injecté des lymphocutes T CD4+ et/ou T CD8+ naïfs isolées à partir de souris transgéniques pour des récepteurs de lymphocytes T spécifiques de HA. Nos résultats montrent que seul le transfert in vivo des cellules tumorales 4T1-HA, et non celui des cellules 4T1 témoins, peut conduire à l'activation, la prolifération et la différentiation des deux types de lymphocytes T spécifiques pour l'antigène HA. De plus, nous avons observé que les populations de lymphocytes T CD4+ et CD8+ sont toutes deux requises, non seulement pour une réponse anti-tumorale efficace, mais aussi pour le déclenchement d'une réaction auto-immune collatérale chez la souris CamK-HA. Enfin, nous avons montré qu'il était nécessaire d'injecter en parallèle des anticorps contre le récepteur inhibiteur CTLA-4 chez la souris L7-HA, afin de permettre la migration des lymphocytes T spécifiques de HA dans le cervelet. Chez ces souris L7-HA, nous avons en outre démontré que les lymphocytes T CD8+ cytotoxiques sont les effecteurs principaux de la maladie. Ces nouveaux modèles murins représentent donc des outils précieux pour une meilleure compréhension des mécanismes moléculaires responsables du développement des SNP. De plus, ils pourraient permettre de tester et de valider de nouvelles approches thérapeutiques visant à bloquer la pénétration dans le SNC d'effecteurs immunitaires potentiellement pathogènes, tout en préservant l'efficacité de la réponse anti-tumorale en périphérie. / Paraneoplastic neurological disorders (PNDs) are rare human autoimmune diseases that mostly affect the central nervous system (CNS). They are triggered by an efficient immune response against a neural self-antigen that is ectopically expressed in neoplastic tumor cells and naturally expressed in CNS cells. Due to this shared antigenic expression, the immune system reacts not only to tumor cells but also to neural cells resulting in neurological damage. Growing data point to a major role of cell-mediated immunity in PNDs associated to autoantibodies against intracellular proteins. However, its precise contribution in the pathogenesis remains unclear. Two illustrative examples of possibly cell-mediated PNDs are the Hu-syndrome, characterized by inflammation and widespread los of neurons, and paraneoplastic cerebellar degeneration (PCD), characterized by the selective loss of Purkinje cells. PCD develops mostly in patients with gynecologic carcinomas that express the Purkinje neuron-specific CDR2 protein whereas most patients with the Hu-syndrome harbor small cell lung cancer expressing the neuron-specific protein HuD. In this context, our study aimed to investigate the impact of anti-tumor cellular immune responses in the development of these PNDs. To this end, we developed two animal models mimicking the Hu-syndrome and PCD. We used a tumor cell line expressing the hemagglutinin (HA) of influenza virus to induce an anti-tumor response in CamK-HA mice, which express HA in CNS neurons and L7-HA mice, which express HA only in cerebellar Purkinje neurons. To promote and track the T cell response against the HA antigen, naïve HA-specific CD8+ and/or CD4+ T cells, originating from TCR-transgenic animals, were transferred into these mice. We demonstrate that HA-expressing tumors, but not control tumors, induce in vivo activation, proliferation and differentiation of naïve HA-specific CD4+ and CD8+ T cells into effector cells. Moreover, the collaboration between these two T cell subsets was needed to control tumor growth and induce CNS inflammation in CamK-HA mice. In L7-HA mice the additional injection of the antibody against the inhibitory receptor CTLA-4 was necessary to allow T cells to enter the cerebellum to cause inflammation and the subsequent destruction of Purkinje neurons. Furthermore, in L7-HA mice we demonstrate that cytotoxic CD8+ T cells are the main effectors driving the disease. Thus, these two new mouse models provide further insights into the cellular mechanisms of PND whereby a potent anti-tumor immunity triggers a cancer-associated autoimmune disease, and may therefore help to develop new therapeutic strategies against PND.

Les lymphocytes B (LB) et les plasmocytes (PC) émergent comme des cellules importantes dans la surveillance immunitaire des tumeurs, même si leur rôle pro- ou anti-tumoral reste activement débattu. Nous avons émis l’hypothèse que cette dualité fonctionnelle de la réponse B pourrait être dictée par l'identité des sous-populations de LB infiltrant la tumeur et/ou par la nature des anticorps (Ac) qu’ils produisent. Dans ce contexte, nous avons montré que les tumeurs du sein et de l’ovaire sont souvent infiltrées par des LB mémoires et des PC exprimant/produisant principalement des IgG ou des IgA. Les IgA sont fortement enrichis dans les tumeurs mammaires in situ, plus précoces, et dans 15-20% des tumeurs invasives, suggérant un rôle différentiel des IgG et des IgA dans la progression tumorale. Les IgA, pouvant être monomériques ou dimériques dans les tumeurs, ciblent en général des antigènes (Ags) différents de ceux des IgG. Nous montrons de plus que les Ags ciblés par les IgA et les IgG sont souvent impliqués dans des fonctions de développement des tissus et d’interaction avec l’ADN, et sont parfois partagés entre patients et entre les types de tumeurs, suggérant leur importance dans la réponse anti-tumorale. En parallèle, grâce à l’étude des tumeurs de patientes souffrant d’un syndrome neurologique paranéoplasique, nous avons pu montrer que l’induction concomitante de PC à IgG et de LT CD8+ cytotoxiques dans la tumeur était liée à des amplifications et/ou des mutations dans les gènes des Ags tumoraux. Ces résultats mettent en évidence l’important des LB et des Ig dans la réponse anti-tumoral, et ouvre des pistes pour rechercher des cibles thérapeutiques en immunothérapie / B and plasma cells are rising as crucial cells in the immune surveillance of tumors, even though their pro- or anti-tumor role is still debated. We argue that this dual functionality of B cells could depend on the identity of tumor-infiltrating B cell subsets and/or by the nature of the antibodies they produce. With that knowledge, we showed that breast and ovarian tumors are usually infiltrated by memory B cells and plasma cells that express and/or produce mainly IgG or IgA. This last class of Ig in highly enriched in in situ carcinomas of the breast, corresponding to earlier tumors, and in 15-20% of invasive tumors, suggesting a differential role of IgG and IgA in tumor progression. IgA, that can be monomeric or dimeric in tumors, often target antigens that differ from those targeted by IgG. We also show that antigens targeted by IgA and IgG in the tumor are often involved in functions related to the development of tissues and DNA interactions, and can be share amongst patients and between breast and ovarian tumors, suggesting their importance in the anti-tumor immune response. In parallel, using tumors from patients suffering from a paraneoplastic neurological syndrome, we established that the concomitant induction of IgG PC and CD8+ cytotoxic T cells in the tumor is associated wth amplifications and/or mutations in the genes of tumor antigens. These results highlight the importance of B cells and Ig in the anti-tumor immune response and give leads to look for new targets in immunotherapy