Angioimmunoblastic T-cell lymphoma (AITL) is a rare type of lymphoid malignancy with most affected patients presenting in their late 60’s with nonspecific symptoms, laboratory signs and advanced stage disease. 78 year old female with history of hypertension presented to the hospital with complaints of dyspnea, dry cough and fatigue of one week duration. She denied having fever, chills, night sweats or recent weight loss. Labs on admission were significant for leukopenia with lymphocytopenia, thrombocytopenia, hyponatremia and hyperglobulinemia. Computer tomography chest and abdomen showed bilateral multifocal lung infiltrates, large left side pleural effusion, diffuse lymphadenopathy and splenomegaly. She was started on empiric antibiotics for community acquired pneumonia. Sputum culture did not identify any offending organism and although thoracentesis was consistent with exudative fluid, microbiology and pathologic studies also did not offer a diagnosis. Fine needle aspiration of a suspicious lymph node was also negative. She was discharged home to complete treatment for pneumonia but over the next two months, she presented on three different occasions with the same respiratory symptoms. Serial thoracentesis thereafter showed chylous fluid that was fast re-accumulating. A repeat flow cytometry of the pleural fluid was concerning for a lymphoproliferative process and subsequent excisional biopsy with molecular studies performed on rearrangement of T-cell receptors resulted in eventual diagnosis of Angioimmunoblastic T-cell lymphoma stage IV due to associated lung involvement. She declined aggressive management and opted for palliative care. Lymphoma presenting with chylothorax is not common due to early diagnosis of most lymphoma but it can be the initial presentation of AITL because most patients present with nonspecific symptoms and lab findings that make diagnosis difficult and delayed. In our patient, eventual diagnosis was three months from initial presentation. This is not ideal because most patients who succumb to the disease tend to do so from progressive worsening nutritional status and immunosuppression that ensues as the disease advances. The recurrent chylothorax seen in our patient is likely a result of tumor burden that obstructed chyle drainage through the thoracic duct and may have resolved with adequate treatment of the disease. Multiple laboratory abnormalities and B-type symptoms in a patient with unclear primary process should prompt workup for a possible neoplastic disease, particularly lymphoma. Clinicians who suspect a lymphoproliferative process in patients with diffuse lymphadenopathy and pulmonary symptoms of unclear etiology should consider getting an excisional tissue biopsy for further diagnostic studies. PCR based studies that assess for cell locality is also helpful in particularly difficult cases.

Le lymphome angioimmunoblastique à cellules T (AITL) est un lymphome périphérique à cellules T agressif dont les symptômes sont la lymphadénopathie et l'hypergammaglobulinémie. Actuellement, les patients atteints du AITL ont des options de thérapeutiques limitées et des résultats cliniques défavorables, avec un taux de survie sur 5 ans d'environ 30%. Les cellules tumorales du AITL proviennent de cellules T CD4+ appelées cellules T auxiliaires folliculaires (Tfh). Les cellules Tfh sont essentielles dans le centre germinatif (GC), où elles facilitent l'expansion et la différentiation des cellules B en plasmocytes. Cette fonction d'aide est soutenue par de nombreuses protéines dérivées des cellules Tfh et des programmes de transcription qui pourraient aussi fonctionner dans les cellules tumorales du AITL. Par conséquent, la perturbation des principaux mécanismes de signalisation soutenant l'identité des cellules Tfh et leurs interactions avec les cellules B pourrait inhiber la croissance du AITL. Des études ont démontré que les cellules hyperactives de type Tfh provoquent une accumulation de cellules immunitaires telles que les cellules B, les plasmocytes et les macrophages dans les tumeurs. Cependant, le microenvironnement du AITL n'a pas été bien étudié et il n'a pas été vérifié si certaines cellules immunitaires pourraient être utilisées pour arrêter la croissance de la tumeur. Bien que l’on trouve des cellules Tfh circulantes dans l’AITL humain, le taux de propagation peut varier d’un patient à l’autre. Ainsi, une possibilité est la présence de mécanismes de surveillance immunitaire s'opposant à la progression de la tumeur. En accord avec cette hypothèse, un signal positif pour la phagocytose nommé SLAMF7 (contrebalancé par la voie inhibitrice CD47-SIRPα) est exprimé dans un sous-ensemble de patients atteints du AITL. Toutefois, la corrélation entre les différents niveaux d'expression du SLAMF7 et l'amélioration des résultats pour les patients n'a pas été étudiée. En utilisant des souris Roquinsan/+, qui développent spontanément l’AITL, nous avons étudié le rôle des mécanismes de signalisation immunitaire dans les cellules tumorales de type Tfh et du microenvironnement tumoral. Nous avons cherché à inhiber les protéines et les voies de signalisation typiques des cellules Tfh dans les tumeurs afin d'évaluer la valeur thérapeutique potentielle. Nous avons aussi étudié le rôle de la phagocytose dépendante des macrophages dans le contexte SLAMF7 et comment la modulation de la signalisation de CD47-SIRPα peut améliorer l'efficacité de la phagocytose des cellules tumorales. Notre hypothèse centrale est qu'en supprimant les programmes fondamentaux des cellules Tfh ou en favorisant l'élimination phagocytaire des cellules tumorales de type Tfh, nous pouvons favoriser la régression de la tumeur. Nous avons démontré que les tumeurs AITL nécessitent des protéines d’identité des cellules Tfh essentielles telles que le facteur de transcription Bcl6 et la protéine adaptatrice SAP, ainsi que la communication entre les cellules T et B (T-B). Même en l'absence de GC classiques, les cellules tumorales de type Tfh ont apporté un soutien aux cellules B. Cela est démontré par des titres élevés d'IgG et l'accumulation de cellules précurseurs des plasmocytes dans les tumeurs. Nous avons trouvé des preuves de l'opposition entre la surveillance immunitaire et l'évasion au sein des tumeurs de type AITL, car les cellules Tfh augmentent l’expression de la molécule inhibitrice CD47 tandis que les macrophages stimulent le niveau de SLAMF7. Les cellules de type AITL ont été phagocytées plus efficacement in vitro quand la signalisation du CD47 était bloquée. En résumé, nous démontrons que les voies de signalisation importantes pour l'identité des cellules Tfh et la communication entre les cellules T et B sont essentielles pour la progression de l’AITL et suggèrent qu’une surveillance immunitaire continue par les macrophages peut influencer l’évolution de la maladie. Des études futures pourraient explorer la possibilité de combiner des inhibiteurs de l'activité des cellules Tfh ou T-B avec des médicaments qui stimulent l'activité phagocytaire antitumorale pour améliorer l'efficacité thérapeutique du traitement. / Angioimmunoblastic T cell lymphoma (AITL) is an aggressive peripheral T cell lymphoma manifesting with symptoms such as generalized lymphadenopathy and hypergammaglobulinemia. Currently, AITL patients have limited treatment options and poor clinical outcomes with a 5-year survival rate around 30%. AITL tumor cells derive from a subset of CD4+ T cell, the T follicular helper (Tfh) cell. Tfh cells are essential in germinal centers (GC), where they facilitate B cell expansion and differentiation into plasma cells. This helper function is supported by numerous Tfh cell-derived proteins and transcriptional programs which may still be operational in AITL tumor cells. Therefore, disrupting key signaling mechanisms sustaining Tfh cell identity and their ability to interact with B cells could inhibit AITL tumor growth. Studies have demonstrated that these hyperactive Tfh-like cells lead to the accumulation of immune cell subsets such as B cells, plasma cells, and macrophages within tumor lymph nodes. Nevertheless, the AITL tumor microenvironment itself has not been well-studied and whether some immune cells could be harnessed to impede tumor growth has not been tested. In human AITL, although circulating Tfh cells have been reported, the rate of tumor spreading can vary between patients. As such, one possibility is the presence of immune surveillance mechanisms opposing tumor progression. In line with this idea, SLAMF7, a positive signal for macrophage-mediated phagocytosis (counterbalanced by the inhibitory CD47-SIRPα pathway), is expressed in a subset of AITL patients. Despite this, whether differing levels of SLAMF7 expression correlates with improved patient outcomes has not been investigated. Using Roquinsan/+ mice, a spontaneous AITL-like mouse model, we addressed the role of immune signaling mechanisms within Tfh-like tumor cells and the surrounding tumor microenvironment that would promote tumor regression. First, we aimed to inhibit signature Tfh cell proteins and downstream signaling pathways in developed AITL-like tumors to evaluate potential therapeutic value. Second, we investigated the role of macrophage-mediated phagocytosis in the context of SLAMF7 and how modulating CD47-SIRPα signaling may enhance the efficiency of AITL tumor cell engulfment. Our central hypothesis is that by removing fundamental Tfh cell supporting programs from tumor cells or by promoting the phagocytic removal of Tfh-like tumor cells we can favour tumor regression and impair future growth. Through this work, we demonstrated that AITL-like tumors continuously require critical Tfh cell identity proteins such as transcription factor Bcl6 and adaptor protein SAP, as well as T cell-B cell (T-B) crosstalk. Importantly, despite the absence of conventional GCs, Tfh-like tumor cells provided functional support to B cells as evidenced by elevated IgG titers and accumulation of plasma cell precursors in tumors. We also found evidence of opposition between immune surveillance and evasion within AITL-like tumors as Tfh-like cells upregulated inhibitory CD47 levels while macrophages increased expression of prophagocytic SLAMF7. Moreover, AITL-like tumor cells were more efficiently phagocytosed in vitro when CD47 signaling was blocked. Taken together, we demonstrate that pathways important for Tfh cell identity and T-B communication are critical for AITL-like disease progression and suggest that ongoing macrophage-mediated immune surveillance may influence disease outcomes. Future studies may explore combining inhibitors of Tfh cell activity or T-B crosstalk along with drugs which boost antitumor phagocytic activity to further improve the therapeutic efficacy of treatment.