Caractérisation du microenvironnement immunitaire au sein des lésions précancéreuses colorectales

La majorité des cancers solides se développent à partir de lésions précancéreuses, appelées polypes dans le cas du cancer colorectal (CCR). Au sein des individus présentant un risque moyen de CCR, certains développent un nombre anormalement élevé de polypes, augmentant leur chance de cancer. L’identification de paramètres associés avec ce fort taux de polype pourrait permettre de mieux comprendre son origine et de mieux prendre en charge cette catégorie de patients. Parmi les facteurs pouvant modifier la carcinogénèse, le système immunitaire présent au sein du microenvironnement tumoral (MET) a été démontré comme capable de prédire la survie et la réponse thérapeutique des patients. Étant donné que la majorité des cancers sont détectés et traités à des stades avancés, le MET immunitaire est bien plus étudié au sein des cancer avancés qu’au sein des lésions précancéreuses. Récemment, des études dans différents types de cancer (dont le CCR) ont mis en évidence que dès les stades précoces de carcinogénèses, le système immunitaire est capable de reconnaitre et éliminer les cellules tumorales, et que les lésions précancéreuses mettent en place des mécanismes permettant d’échapper à cette réponse immunitaire. Nous avons caractérisé le MET immunitaire au sein d’une cohorte de 26 patients de risque moyen (pour un total de 131 polypes) via une approche intégrative. Nous avons démontré que les patients présentant un faible taux de polype présentaient un infiltrat immunitaire plus important ainsi qu’une plus forte présence de structures immunitaires matures. Nos résultats suggèrent qu’un fort taux de polype pourrait être associé avec une défaillance de la réponse immunitaire local.Most solid cancers develop from precancerous lesions, called polyps in colorectal cancer (CRC). Among average-risk individuals, some patients will develop an abnormally high number of polyps, increasing the likelihood of CRC. Identifying parameters associated with these patients could lead to a better understanding of the mechanisms underlying these high rates of polyp development and implement a more appropriate patient follow-up.Among the factors shaping the carcinogenesis process, the immune system present in the tumor microenvironment (TME) have been shown capable to help predict survival and therapeutic response of cancer patients. As cancers are usually detected and surgically removed at advanced stages, immune TME in precancerous lesions is understudied compared to invasive stages. Recently, studies in various types of cancer (including CRC) demonstrated that the immune system is able to recognize and eliminate tumor cells even at the earlier stages of carcinogenesis, and that precancerous lesions are able to develop mechanisms leading to immune escape.We took advantage of a cohort of 26 average-risk patients (and a total of 131 polyps) who presented a heterogeneous frequency rate to perform an integrative approach to characterize the TME of polyps. We demonstrated that patients with a low polyp development rate were associated with a higher presence of mature immune structure in the TME and higher levels of immune infiltrate in general. Our data suggest that a higher rate of polyp development could be associated with a defect of the local immune response, potentially paving the way for immunotherapy management of these patients

Immunoproteasomes Control the Homeostasis of Medullary Thymic Epithelial Cells by Alleviating Proteotoxic Stress

The sole nonredundant role of the thymic medulla is to induce central tolerance, a vital process that depends on promiscuous gene expression (pGE), a unique feature of medullary thymic epithelial cells (mTECs). Although pGE enhances transcription of >3,000 genes in mTECs, its impact on the regulation of protein homeostasis remains unexplored. Here, we report that, because of pGE, mature mTECs synthesize substantially more proteins than other cell types and are exquisitely sensitive to loss of immunoproteasomes (IPs). Indeed, IP deficiency causes proteotoxic stress in mTECs and leads to exhaustion of postnatal mTEC progenitors. Moreover, IP-deficient mice show accelerated thymic involution, which is characterized by a selective loss of mTECs and multiorgan autoimmune manifestations. We conclude that pGE, the quintessential feature of mTECs, is a major burden for the maintenance of proteostasis, which is alleviated by the constitutive expression of IPs in mTECs

Evolution of Metastases in Space and Time under Immune Selection.

We examined how the immune microenvironment molds tumor evolution at different metastatic organs in a longitudinal dataset of colorectal cancer. Through multiplexed analyses, we showed that clonal evolution patterns during metastatic progression depend on the immune contexture at the metastatic site. Genetic evidence of neoantigen depletion was observed in the sites with high Immunoscore and spatial proximity between Ki67 tumor cells and CD3 cells. The immunoedited tumor clones were eliminated and did not recur, while progressing clones were immune privileged, despite the presence of tumor-infiltrating lymphocytes. Characterization of immune-privileged metastases revealed tumor-intrinsic and tumor-extrinsic mechanisms of escape. The lowest recurrence risk was associated with high Immunoscore, occurrence of immunoediting, and low tumor burden. We propose a parallel selection model of metastatic progression, where branched evolution could be traced back to immune-escaping clones. The findings could inform the understanding of cancer dissemination and the development of immunotherapeutics

Immunoscore immune checkpoint using spatial quantitative analysis of CD8 and PD-L1 markers is predictive of the efficacy of anti- PD1/PD-L1 immunotherapy in non-small cell lung cancer

International audienceBackground Anti-PD-1 and PD-L1 antibodies (mAbs) are approved immunotherapy agents to treat metastatic non-small cell lung cancer (NSCLC) patients. Only a minority of patients responds to these treatments and biomarkers predicting response are currently lacking. Methods Immunoscore-Immune-Checkpoint (Immunoscore-IC), an in vitro diagnostic test, was used on 471 routinesingle FFPE-slides, and the duplex-immunohistochemistry CD8 and PD-L1 staining was quantified using digital-pathology. Analytical validation was performed on two independent cohorts of 206 NSCLC patients. Quantitative parameters related to cell location, number, proximity and clustering were analysed. The Immunoscore-IC was applied on a first cohort of metastatic NSCLC patients (n = 133), treated with anti-PD1 or anti-PD-L1 mAbs. Another independent cohort (n = 132) served as validation. Findings Anti-PDL1 clone (HDX3) has similar characteristics as anti-PD-L1 clones (22C3, SP263). Densities of PD-L1+ cells, CD8+ cells and distances between CD8+ and PD-L1+ cells were quantified and the Immunoscore-IC classification was computed. Using univariate Cox model, 5 histological dichotomised variables (CD8 free of PD-L1+ cells, CD8 clusters, CD8 cells in proximity of PD-L1 cells, CD8 density and PD-L1 cells in proximity of CD8 cells) were significantly associated with Progression-Free Survival (PFS) (all P < 0.0001). Immunoscore-IC classification improved the discriminating power of prognostic model, which included clinical variables andpathologist PD-L1 assessment. In two categories, the Immunoscore-IC risk-score was significantly associated with patients’ PFS (HR = 0.39, 95% CI (0.26–0.59), P < 0.0001) and Overall Survival (OS) (HR = 0.42, 95% CI (0.27–0.65), P < 0.0001) in the training-set. Further increased hazard ratios (HR) were found when stratifying patients into three-category Immunoscore-IC (IS-IC). All patients with Low-IS-IC progressed in less than 18 months, whereas PFS at 36 months were 34% and 33% of High-IS-IC patients in the training and validation sets, respectively.Interpretation Immunoscore-IC is a powerful tool to predict the efficacy of immune-checkpoint inhibitors (ICIs) inpatients with NSCLC