L'immunothérapie basée sur le blocage des points de contrôle immunitaire (ICBs) est un traitement prometteur pour les patients atteints de mélanome ; cependant, seule une petite sous-population en tire un bénéfice à long terme. Un des défis pour améliorer l'efficacité et étendre le bénéfice des ICBs aux patients non répondeurs est de concevoir des approches innovantes permettant de transformer les tumeurs dites "froides ou désertes pour les cellules immunitaire" en tumeurs dites "chaudes ou infiltrées par les cellules immunitaires" qui sont éligibles aux ICBs. Nous avons étudié l'impact du ciblage du gène de l'autophagie Beclin1 sur le paysage immunitaire des tumeurs de mélanome B16-F10. Nos résultats ont démonté que ce ciblage inhibait significativement la croissance tumorale B16-F10 et augmentait l'infiltration des leucocytes CD45+. Le phénotypage immunitaire a révélé une augmentation de l'infiltration de cellules NK (Natural Killer) actives, de macrophages inflammatoires et résidents de type 1, de cellules dendritiques et de lymphocytes T CD8+ actifs. L’inhibition de la croissance tumorale Becn1- n'était plus observée par la déplétion des CD8+ de l'hôte, soulignant ainsi leur rôle dans le contrôle du développement de ces tumeurs. Nos résultats ont démontré que La régulation du paysage immunitaire des tumeurs Becn1- était associée à une modulation du réseau de cytokines/chémokines dans le microenvironnement tumoral (TME). Ainsi, les tumeurs Becn1- présentaient une signature de cytokines inflammatoires (comprenant CCL5, CXCL10 et IFNg) qui pourrait être responsable de l'établissement de microenvironnement inflammatoire permissif aux cellules CD8. Nous avons révélé que la surexpression de l'IFNg dans le TME des tumeurs Becn1- était responsable de l'induction de PD-L1 sur les cellules tumorales par la voie d'activation JAK/STATs. En conclusion, cette étude met en évidence Beclin1 comme une cible majeure, capable d'induire l'infiltration des cellules effectrices immunitaires dans les mélanomes en induisant une signature inflammatoire. Elle fournit également la preuve de concept pour combiner des inhibiteurs d'autophagie avec les ICBs comme une approche de pointe pour améliorer leur efficacité. / Immune Checkpoint Blockades (ICBs)-based immunotherapy has emerged as a promising treatment for melanoma patients; however only a small subset of patients reaps a long term benefit. One of the major challenges to enhance the efficacy and extend the benefit of ICBs to non-responder patients is to design innovative approaches allowing the switch of “immune desert cold tumors” to “immune infiltrated hot tumors" which are eligible for ICB-based therapies. Here, we investigated the impact of targeting the early autophagy gene Beclin1 on the immune landscape of B16-F10 melanoma tumors. We found that targeting Beclin1 (Becn1-) significantly inhibited B16-F10 tumor growth and increased the infiltration of CD45+ leukocytes into the tumor bed. Immune phenotyping revealed an increased infiltration of active Natural Killer (NK) cells, inflammatory and resident type 1 macrophages, dendritic cells, and active CD8+ T lymphocytes. The inhibition of Becn1- tumor growth was no longer observed by depleting host CD8+ T cells, thus highlighting their major role in the control of Becn1- B16-F10 tumor development. We showed that Beclin1-dependent regulation of the immune landscape was associated with profound modulation of the cytokine/chemokine network in the tumor microenvironment (TME). Importantly, we revealed that Becn1- tumors displayed an inflammatory cytokine signature (comprised, but not restricted to, CCL5, CXCL10 and IFNg) that could be responsible for the switch from cold non T-inflamed to hot T-inflamed tumors. Mechanistically, we reported that the overexpression of IFNg in Becn1- TME was responsible for the induction of Programed Death ligand-1 (PD-L1) on tumor cells through the activation of JAK/STATs pathway. Overall, this study highlights Beclin1 as a valuable target, able to drive immune effectors cells into the melanoma tumors by inducing an inflammatory signature. This study provides the proof of concept for combining drugs inhibiting early autophagy process along with ICBs as a cutting-edge approach to improve their efficacy.

Progression through the cell cycle is tightly controlled, and the decision whether or not to enter a new cell cycle can be influenced by both internal and external cues. For budding yeast one such external cue is pheromone treatment, which can induce G1 arrest. Two distinct mechanisms are known to be involved in this arrest, one dependent on the arrest protein Far1 and one independent of Far1, but the exact mechanisms have remained enigmatic. The studies presented here further elucidate both of these mechanisms. We looked at two distinct aspects of the Far1-independent arrest mechanism. First, we studied the role of the G1/S regulatory system in G1 arrest. We found that deletion of the G1/S transcriptional repressors Whi5 and Stb1 compromises Far1-independent arrest, but only partially, and that this partial arrest failure correlates to partial de-repression of G1/S transcripts. Deletion of the CKI Sic1, however, is more strongly required for arrest in the absence of Far1, though not when Far1 is present. Together, this demonstrates that functionally overlapping regulatory circuits controlling the G1/S transition collectively provide robustness to the G1 arrest response. We also sought to reexamine the phenomenon of pheromone-induced loss of G1/S cyclin proteins, which we suspected could be another Far1-independent arrest mechanism. We confirmed that pheromone treatment has an effect on G1 cyclin protein levels independent of transcriptional control. Our findings suggest that this phenomenon is dependent on SCFGrr1but is at least partly independent of Cdc28 activity, the CDK phosphorylation sites in Cln2, and Far1. We were not, however, able to obtain evidence that pheromone increases the degradation rate of Cln1/2, which raises the possibility that pheromone reduces their synthesis rate instead. Finally, we also studied the function of Far1 during pheromone-induced G1 arrest. Although it has been assumed that Far1 acts as a G1/S cyclin specific CDK inhibitor, there has been no conclusive evidence that this is the case. Our data, however, suggests that at least part of Far1’s function may actually be to interfere with Cln-CDK/substrate interactions since we saw a significant decrease of co-pulldown of Cln2 and substrates after treatment with pheromone. All together, the results presented here demonstrate that there are numerous independent mechanisms in place to help robustly arrest cells in G1.

The coordination between cell growth and division is a highly regulated process that is intimately linked to the cell cycle. Efforts to identify an independent mechanism that measures cell size have been unsuccessful. Instead, we propose that size control is an intrinsic function of the basic cell cycle machinery. My work shows that in the fission yeast Schizosaccharomyces pombe Cdc25 accumulates in a size dependent manner. This accumulation of Cdc25 occurs over a large range of cell sizes. Additionally, experiments with short pulses of cycloheximide have shown that Cdc25 is an inherently unstable protein that quickly returns to a size dependent equilibrium in the cell suggesting that Cdc25 concentration is dependent on size and not time. Thus, Cdc25 can act as a sizer for the cell. However, cells are still viable when Cdc25 is constitutively expressed suggesting that there is another sizer in the case that Cdc25 expression is compromised. Cdc13 is a likely candidate due to the similar characteristics to Cdc25 and the ability to activate Cdc2. Cdc13 accumulates during the cell cycle in a manner similar to Cdc25. I show that in the absence of Cdc2 tyrosine phosphorylation, the cell size is sensitive to Cdc13 activity showing that Cdc13 accumulation can determine when cells enter mitosis. These results suggest a two sizer model where Cdc25 is the main sizer with Cdc13 acting as a backup sizer in the event of Cdc25 expression is compromised. Additionally, in the absence of Cdc2 phosphorylation by the kinases Wee1 and Mik1, mitotic entry is regulated by the activity of Cdc2. In the absence of Cdc2 phosphorylation, this activity is regulated by binding of cyclins to Cdc2. Under these circumstances, the activity of Cdc13 can regulate mitotic entry provide further evidence that Cdc13 could be a sizer of the cell in the case where Cdc25 expression is compromised. The results I present in this dissertation provide the groundwork for understanding how cells regulate size and how this size regulation affects cell cycle control in S. pombe . The results show how the intrinsic cell cycle machinery can act as a sizer for the G2/M transition in S. pombe . Interestingly, this mitotic commitment pathway is well conserved suggesting a general solution for size control in eukaryotes at the G2/M transition. Understanding the mechanism of how protein concentration is regulated in a size dependent manner will give much needed insight into how cells control size. Elucidating the mechanism for size control will capitalize on decades of research and deepen our understanding of basic cell biology.

<p>Modern information technology increases the use of computers in training systems as well as in command-and-control systems in military services and public-safety organizations. This computerization combined with new threats present a challenging complexity. Situational awareness in evolving distributed operations and follow-up in training systems depends on humans in the field reporting observations of events. The use of this observer-reported information can be largely improved by implementation of models supporting both reporting and computer representation of objects and phenomena in operations.</p><p>This thesis characterises and describes observer model-based data collection in distributed tactical operations, where multiple, dispersed units work to achieve common goals. Reconstruction and exploration of multimedia representations of operations is becoming an established means for supporting taskforce training. We explore how modelling of operational processes and entities can support observer data collection and increase information content in mission histories. We use realistic exercises for testing developed models, methods and tools for observer data collection and transfer results to live operations.</p><p>The main contribution of this thesis is the systematic description of the model-based approach to using observers for data collection. Methodological aspects in using humans to collect data to be used in information systems, and also modelling aspects for phenomena occurring in emergency response and communication areas contribute to the body of research. We describe a general methodology for using human observers to collect adequate data for use in information systems. In addition, we describe methods and tools to collect data on the chain of medical attendance in emergency response exercises, and on command-and-control processes in several domains.</p>

Made available in DSpace on 2016-06-02T19:52:04Z (GMT). No. of bitstreams: 1 5927.pdf: 1158172 bytes, checksum: da512af227afdf83a621e75580a2a3de (MD5) Previous issue date: 2014-03-27 / Financiadora de Estudos e Projetos / The changing in the labor dynamics of the sugarcane harvesting, occasioned by integration of mechanical harvesters, has subjected workers to new working conditions, increasing the interactions with machines, and consequently causing new diseases and work accidents. For improving the performance of work so that this becomes less destructive of human capabilities, is important the use of instruments that allow the identification of risks from man-labor ratio, which are identified through the study of literature in Ergonomics. This study aimed to verify the applicability of the checkpoints of the instrument Ergonomic Checkpoints in Agriculture to the work situation in the context of mechanized harvesting of cane sugar. A review of the relevant issues related to the study was accomplished, considering the themes: Ergonomics, ergonomic analysis tools and working conditions; process of mechanized production of cane sugar, with a focus on the process of harvesting and working conditions; and, finally, the study of the instrument Ergonomic Checkpoints in Agriculture. Subsequently, the analysis of the instrument was accomplished, which was constituted of the following principal stages. Initially, the checkpoints of the instrument were classified considering the workloads, and the similarity of content. Posteriorly, the checkpoints were analysed with respect the applicability in the job functions found in mechanical harvesting of cane sugar process. As a result, 84 checkpoints were classified into 23 clusters and 16 checkpoints were not grouped, among which 11 clusters and 8 checkpoints, which represent 53% of the content of the instrument, were identified with potential of application in the sugarcane mechanical harvesting. The checkpoints identified may assist in the evaluation and implementation of better working conditions, considering the ergonomic point of view, in the mechanical harvesting of sugarcane. / A mudança na dinâmica de trabalho no processo de colheita da cana-de-açúcar, através da crescente inserção de colhedoras mecânicas, tem submetido os trabalhadores a novas condições de trabalho, que inclui a interação com máquinas e equipamentos, ocasionando doenças ocupacionais. Para melhoria das condições de realização do trabalho de forma que esse se torne menos destrutivo das capacidades humanas, é necessária a utilização de instrumentos que permitam a identificação de riscos provenientes da relação homem-trabalho, que são identificados através do estudo da literatura em Ergonomia. Este trabalho objetivou verificar a aplicabilidade dos pontos de verificação do instrumento Ergonomic Checkpoints in Agriculture à situação de trabalho no contexto da colheita mecanizada da cana-de-açúcar. Foi realizada uma revisão sobre os temas relevantes que envolvem o estudo, isto é: Ergonomia, instrumentos de análise ergonômica e condições de trabalho; processo de produção mecanizada da cana-de-açúcar, com enfoque no processo de colheita e nas condições de trabalho advindas deste processo; e, estudo do instrumento Ergonomic Checkpoints in Agriculture. Posteriormente, foi realizada a análise do instrumento, que se constituiu das etapas de classificação dos pontos de verificação do instrumento por cargas de trabalho, por similaridade de conteúdo, e da análise da aplicabilidade dos pontos de verificação considerando as características e as funções de trabalho encontradas no processo de colheita mecanizada da cana-de-açúcar. Como resultados, 84 pontos de verificação foram classificados em 23 agrupamentos e 16 pontos de verificação não foram agrupados, dentre os quais foram identificados 11 agrupamentos e 8 pontos de verificação aplicáveis, que representam 53% do conteúdo do instrumento. Os pontos de verificação identificados podem auxiliar na avaliação e implementação de melhores condições de trabalho, do ponto de vista ergonômico, na colheita mecanizada da cana-de-açúcar.

L’adénocarcinome canalaire du pancréas (ACP) est un problème majeur de santé publique. L’ACP se développe principalement à partir de deux lésions précurseurs : les néoplasies intra-épithéliales pancréatiques et les tumeurs intracanalaires papillaires et mucineuses du pancréas (TIPMP). Les mécanismes moléculaires sous-tendant l’oncogenèse pancréatique sont nombreux. Nous avons étudié le mécanisme de cancérogenèse MSI (MicroSatellite Instability) où il existe une déficience dans le système de réparation des erreurs de réplication de l’ADN ou système MMR (Mismatch Repair). Ce mécanisme de cancérogenèse original est caractérisé par une instabilité génétique de l’ADN affectant les séquences répétées microsatellites du génome. Le phénotype MSI a été décrit dans le syndrome de Lynch (SL), dans lequel il existe une mutation germinale d’un des gènes du système MMR (MLH1, MSH2, MSH6 et PMS2). L’intérêt de l’étude des cancers MSI s’est accru de façon considérable avec le développement des immunothérapies dirigées contre les checkpoints immunitaires (ICK), en particulier PD-1/PD-L1. Nous avons confirmé que la fréquence du phénotype MSI se situe entre 1-2%. Nous avons montré que l’immunohistochimie est la méthode de screening plus adaptée pour l’identification de l’ACP MSI en comparaison avec les techniques de biologie moléculaire. Le phénotype MSI a été plus fréquemment observé dans un contexte de TIPMP. Les cas MSI identifiés présentaient des caractéristiques biologiques évocatrices du SL. Egalement, nos résultats confirment la présence d’un processus de carcinogenèse MSI immunogénique, mais suggèrent des évènements somatiques spécifiques à l’organe d’origine du cancer. Par ailleurs, les ACP MSI étaient caractérisés par un infiltrat inflammatoire riche en lymphocytes cytotoxiques T CD8+ et surexprimaient l’ICK PD-L1 permettant de supposer une probable réponse clinique de l’ACP MSI à l’immunothérapie anti-PD1/PD-L1. / Pancreatic ductal adenocarcinoma (PDAC) is a major health problem in France and around the world. PDAC is developed mainly from two precursor lesions: pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm (IPMN). There are several molecular mechanisms underlying pancreatic oncogenesis. Particularly, we were interested in the MSI (MicroSatellite Instability) which is due to a defective DNA Mismatch Repair (MMR) system, which normally functions to recognize and repair erroneous insertions, deletions, and mis-incorporation of bases that can arise during DNA replication and recombination. The MSI phenotype was first described in the familial cancer condition known as Lynch syndrome (LS), where the MMR genes MLH1, MSH2, MSH6 or PMS2 harbor germline mutations. Interest in MSI tumors has recently increased after studies have highlighted the concomitant expression of multiple active immune checkpoint (ICK) markers including PD-1 and PD-L1 and the role of the MSI status to predict clinical benefit from immune checkpoint blockade. A Our results indicate that the MSI phenotype occurs in PDAC with a frequency of 1-2%. Our data showed that IHC using antibodies against the four MMR proteins was more sensitive for the assessment of MSI status than PCR-based methods. In addition, we demonstrate for the first time a statistically significant positive association between MSI and IPMNs in PDAC. MSI PDAC, including IPMN, are unlikely to be sporadic since they display molecular features that are usually observed in LS-related neoplasms. Also, our results highlight that an MSI-driven immunogenic pathway to cancer is active in MSI PDACs but suggest that MSI-driven somatic events may be tissue-specific. We observed a stronger lymphocytic tumor infiltration by activated TCD8 cells in MSI PDAC compared to MSS PDAC and found a positive association between PD-L1 expression and MSI status, suggesting that MSI PDAC could be responsive to ICK blockade therapy.

Une tumeur est un environnement complexe comprenant à la fois des composants immunitaires et non immunitaires. Dans notre équipe, nous avons démontré précédemment le rôle des structures lymphoïdes tertiaires (TLS) dans les cancers du poumon, dans la génération de réponses anti-tumorales protectrices. Cependant, les tumeurs peuvent se développer en utilisant des mécanismes d’immunosuppression tels que l’infiltration des cellules T régulatrices (Tregs) dans le microenvironnement tumoral. Cette thèse a étudié le mécanisme présumé des Tregs dans la régulation des réponses immunitaires dans le cancer du poumon. Cette étude démontre la présence de Tregs FoxP3+ dans les TLS aussi bien que dans les autres régions tumorales. Les Tregs infiltrant la tumeur (Ti-Tregs) présentent un phénotype de lymphocytes T à mémoire centrale, et effecteur mémoire. Ces cellules expriment un vaste répertoire de molécules d’activation et de « chekpoints » immunologiques. L’analyse de l’expression des gènes et des résultats de cytométrie en flux a montré que les Tregs expriment des marqueurs de co-stimulation et de co-inhibition. Une forte densité de Ti-Tregs dans les TLS ou les autres régions tumorales, est associée à une faible survie des patients. Lorsqu’on combine ce résultat avec la densité de DC matures ou lymphocytes B associés aux TLS ou CD8+, un groupe de patients présentant de faible densités de ces cellules mais de fortes densités en Tregs a le pronostic le moins favorable avec le plus grand risque de décès. Les Tregs créent un environnement immunosuppresseur dans les cancers pulmonaires. Ce mécanisme pourrait être une explication de la réduction observée de la survie de ces patients. / Tumor comprise complex niche of the immune and non-immune components. The complex interaction between the tumor cells with its environment turns into either eradication or the growth and metastasis of the tumors. We have previously demonstrated the role of TLS (tertiary lymphoid structures) in lung tumors, in protective anti-tumor responses. Despite of this, tumors do develop via exploiting the regulatory mechanisms, particularly includes, infiltration of the Tregs (regulatory T cells). The aim of thesis was to study the putative role of Tregs in regulating the immune responses in lung cancer. This study strongly demonstrates the presence of FoxP3+ Tregs in the TLS as well as non-TLS areas of the lung tumors. Tregs mainly exhibit central and effector memory phenotype expressing vast repertoire of the activation and immune checkpoint molecules. The gene expression and flow cytometry data showed that Tregs express the co-stimulatory and inhibitory markers which are known to be involved in the their activation and immune suppression. The high density of the Ti-Tregs either in TLS or in nonTLS areas is associated with the poor survival of the NSCLC patients. When combined with the density of TLS mature DC or B cells or CD8+ T cells, a group of patients with the low DC, B cells and CD8+ T cells but high Tregs densities, had the worst clinical outcome. This allowed, to identify the NSCLC patients with highest risk of death. Thus, it be concluded that the Tregs create the immunosuppressive environment in the lung tumors by acting in both TLS and nonTLS areas of the tumors and thus could be possible reason for the reduced survival of the lung cancer patients.

Malgré les avancées thérapeutiques récentes, le pronostic des patients porteurs de métastases osseuses (MO) reste faible, ce qui incite à chercher des nouvelles stratégies thérapeutiques. Les chimiokines sont des acteurs majeurs de la réponse immune, et apparaissent comme des cibles potentielles de l’immunothérapie anti-cancéreuse. Nous avons recherché à définir si la chimiokine CX3CL1 pouvait représenter un axe thérapeutique efficace dans le contexte des MO. Pour cela nous avons développé des modèles murins de MO de cancer du rein et du poumon. Dans le modèle de MO de cancer du poumon, notre travail a démontré que l'expression de CX3CL1 inhibe la croissance tumorale. L’analyse transcriptomique des tumeurs a montré que CX3CL1 diminue (i) l’ostéloyse via un effet sur la triade OPG/RANKL/RANK (ii) l'expression de certains checkpoints, en faveur d’une réponse immune antitumorale. En revanche, dans le modèle de MO de cancer du rein, l’expression de CX3CL1 stimule le développement tumoral et l'ostéolyse via une action sur la triade OPG/RANKL/RANK et inhibe la réponse immune antitumorale via une augmentation de l'expression de certains checkpoints immunitaires. Les bisphosphonates (BPs) sont des agents utilisés pour le traitement des MO. Afin de réduire leurs effets indésirables, nous avons utilisé des ciments de phosphate de calcium (CPC), pour délivrer localement dans l’os des BPs (alendronate, ALN). Notre travail a mis en évidence que (i) ces ciments chargés en ALN relarguent en continue les BPs, (ii) le relarguage d’ALN est efficace pour induire des effets cytotoxiques et pro-apoptotiques vis à vis des cellules de cancer du sein / Despite recent therapeutic improvments, the prognosis for a patient with bone metastases (BM) remains poor, this situation prompting the research of new therapeutic strategies. Chemokines are central players in the immune response, and appear as potential targets in anti-cancer immunotherapies. We are interested to determine whether the CX3CL1 chemokine exerted pro or anti-tumor actions within the bone metastatic context. To address this issue, we developed mouse models of lung or renal cancer BM. In lung cancer BM model, our work demonstrated that CX3CL1 expression led to tumor growth inhibition. Tumors transcriptomic analysis revealed that CX3CL1: (i) impacted bone metabolism by modulating the OPG/RANKL/RANK triad (ii) decreased the expression of certain immune checkpoints, this up-regulating the anti-tumor immune response. By contrast, in renal cancer BM model, CX3CL1 expression stimulated bone tumor development and transcriptomic analysis showed that CX3CL1 (i) promoted osteolysis through an action on the OPG/RANKL/RANK triad (ii) -induced tumor development correlated with an increased expression of certain immune checkpoints, this down-regulating the anti-tumor immune response. Bisphosphonates (BPs) are targeted agents used for BM treatment. In order to reduce their side effects, we used resorbable calcium phosphate cements (CPC), which are frequently used as bone void fillers, as platform for a local delivery of BPs (alendronate, ALN). As a whole, our in vitro data demonstrated that: (i) ALN-CPC cements continuous released ALN; (ii) this ALN release was effective in inducing cytotoxic and pro-apoptotic effects in breast cancer cells

Modern information technology increases the use of computers in training systems as well as in command-and-control systems in military services and public-safety organizations. This computerization combined with new threats present a challenging complexity. Situational awareness in evolving distributed operations and follow-up in training systems depends on humans in the field reporting observations of events. The use of this observer-reported information can be largely improved by implementation of models supporting both reporting and computer representation of objects and phenomena in operations. This thesis characterises and describes observer model-based data collection in distributed tactical operations, where multiple, dispersed units work to achieve common goals. Reconstruction and exploration of multimedia representations of operations is becoming an established means for supporting taskforce training. We explore how modelling of operational processes and entities can support observer data collection and increase information content in mission histories. We use realistic exercises for testing developed models, methods and tools for observer data collection and transfer results to live operations. The main contribution of this thesis is the systematic description of the model-based approach to using observers for data collection. Methodological aspects in using humans to collect data to be used in information systems, and also modelling aspects for phenomena occurring in emergency response and communication areas contribute to the body of research. We describe a general methodology for using human observers to collect adequate data for use in information systems. In addition, we describe methods and tools to collect data on the chain of medical attendance in emergency response exercises, and on command-and-control processes in several domains.

The administration of antibodies blocking the immune checkpoint molecules programmed cell death protein 1 (PD-1) or programmed cell death 1 ligand 1 (PD-L1) has evolved as a very promising treatment option for cancer patients. PD-1/PD-L1 inhibition has significantly enhanced expansion, cytokine secretion, and cytotoxic activity of CD4+ and CD8+ T lymphocytes, resulting in enhanced antitumor responses. Anti-PD-1 or anti-PD-L1 therapy has induced tumor regression and improved clinical outcome in patients with different tumor entities, including melanoma, non-small-cell lung cancer, and renal cell carcinoma. These findings led to the approval of various anti-PD-1 or anti-PD-L1 antibodies for the treatment of tumor patients. However, the majority of patients have failed to respond to this treatment modality. Comprehensive immune monitoring of clinical trials led to the identification of potential biomarkers distinguishing between responders and non-responders, the discovery of modes of treatment resistance, and the design of improved immunotherapeutic strategies. In this review article, we summarize the evolving landscape of biomarkers for anti-PD-1 or anti-PD-L1 therapy.