The Experts below are selected from a list of 6603 Experts worldwide ranked by ideXlab platform
Mark J. Smyth - One of the best experts on this subject based on the ideXlab platform.
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Cancer Immunoediting and immune dysregulation in multiple myeloma.
Blood, 2020Co-Authors: Kyohei Nakamura, Mark J. Smyth, Ludovic MartinetAbstract:Avoiding immune destruction is a hallmark of cancer. Over the past few years, significant advances have been made in understanding immune dysfunction and immunosuppression in multiple myeloma (MM), and various immunotherapeutic approaches have delivered improved clinical responses. However, it is still challenging to completely eliminate malignant plasma cells (PCs) and achieve complete cure. The interplay between the immune system and malignant PCs is implicated throughout all stages of PC dyscrasias, including asymptomatic states called monoclonal gammopathy of undetermined significance and smoldering myeloma. Although the immune system effectively eliminates malignant PCs, or at least induces functional dormancy at early stages, malignant PCs eventually evade immune elimination, leading to progression to active MM, in which dysfunctional effector lymphocytes, tumor-educated immunosuppressive cells, and soluble mediators coordinately act as a barrier for antimyeloma immunity. An in-depth understanding of this dynamic process, called cancer Immunoediting, will provide important insights into the immunopathology of PC dyscrasias and MM immunotherapy. Moreover, a growing body of evidence suggests that, together with nonhematopoietic stromal cells, bone marrow (BM) immune cells with unique functions support the survival of normal and malignant PCs in the BM niche, highlighting the diverse roles of immune cells beyond antimyeloma immunity. Together, the immune system critically acts as a rheostat that fine-tunes the balance between dormancy and disease progression in PC dyscrasias.
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Immunoediting of cancer metastasis by NK cells
Nature Cancer, 2020Co-Authors: Kyohei Nakamura, Mark J. SmythAbstract:Natural killer (NK) cells serve a critical role in the control of metastasis. NK cells are now shown to preferentially control monoclonal metastases derived from single circulating tumor cells rather than polyclonal metastases derived from cell clusters. These findings provide further evidence that NK cells are linked to metastatic cell Immunoediting.
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Innate Cancer Immunoediting
The Journal of investigative dermatology, 2020Co-Authors: Tobias Bald, Mark J. SmythAbstract:Immune cells detect and destroy cancer cells; however, very early changes in cancer genome and phenotype coupled with immune system selection cause escape variant survival in a process called cancer Immunoediting. Although adaptive immunity is important for this process, the report by Kubick et al. provides novel insights into the role of innate immune cells for Immunoediting of early transformed epithelial cells.
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Cancer Immunoediting and resistance to T cell-based immunotherapy.
Nature reviews. Clinical oncology, 2018Co-Authors: Jake S. O’donnell, Michele W.l. Teng, Mark J. SmythAbstract:Anticancer immunotherapies involving the use of immune-checkpoint inhibitors or adoptive cellular transfer have emerged as new therapeutic pillars within oncology. These treatments function by overcoming or relieving tumour-induced immunosuppression, thereby enabling immune-mediated tumour clearance. While often more effective and better tolerated than traditional and targeted therapies, many patients have innate or acquired resistance to immunotherapies. Cancer Immunoediting is the process whereby the immune system can both constrain and promote tumour development, which proceeds through three phases termed elimination, equilibrium and escape. Throughout these phases, tumour immunogenicity is edited, and immunosuppressive mechanisms that enable disease progression are acquired. The mechanisms of resistance to immunotherapy seem to broadly overlap with those used by cancers as they undergo Immunoediting to evade detection by the immune system. In this Review, we discuss how a deeper understanding of the mechanisms underlying the cancer Immunoediting process can provide insight into the development of resistance to immunotherapies and the strategies that can be used to overcome such resistance.
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From mice to humans: developments in cancer Immunoediting
The Journal of clinical investigation, 2015Co-Authors: Michele W.l. Teng, Jérôme Galon, Wolf-herman Fridman, Mark J. SmythAbstract:Cancer Immunoediting explains the dual role by which the immune system can both suppress and/or promote tumor growth. Although cancer Immunoediting was first demonstrated using mouse models of cancer, strong evidence that it occurs in human cancers is now accumulating. In particular, the importance of CD8+ T cells in cancer Immunoediting has been shown, and more broadly in those tumors with an adaptive immune resistance phenotype. This Review describes the characteristics of the adaptive immune resistance tumor microenvironment and discusses data obtained in mouse and human settings. The role of other immune cells and factors influencing the effector function of tumor-specific CD8+ T cells is covered. We also discuss the temporal occurrence of cancer Immunoediting in metastases and whether it differs from Immunoediting in the primary tumor of origin.
Robert D. Schreiber - One of the best experts on this subject based on the ideXlab platform.
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Cancer Immunosurveillance: Immunoediting
Encyclopedia of Immunobiology, 2016Co-Authors: Danielle M. Lussier, Robert D. SchreiberAbstract:Cancer Immunoediting is the process wherein immunity not only protects against cancer development but also promotes outgrowth of cancers capable of escaping immune control. As an extrinsic tumor suppressor, immunity exerts selective pressure on developing cancers that can favor outgrowth of cancer cells with reduced immunogenicities. The tumor sculpting action of immunity is a consequence of T cell–dependent immunoselection and/or epigenetic mechanisms that specifically target cancer cells expressing highly immunogenic cancer antigens including tumor-specific mutant neoantigens. Cancer Immunoediting thus serves as a conceptual framework that explains the complex interactions that occur between the immune system and developing cancers.
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new insights into cancer Immunoediting and its three component phases elimination equilibrium and escape
Current Opinion in Immunology, 2014Co-Authors: Deepak Mittal, Robert D. Schreiber, Mark J. Smyth, Matthew M. GubinAbstract:The principles of cancer Immunoediting have set the foundations for understanding the dual host-protective and tumour sculpting actions of immunity on cancer and establishing the basis for novel individualized cancer immunotherapies. During cancer Immunoediting, the host immune system shapes tumour fate in three phases through the activation of innate and adaptive immune mechanisms. In the first phase, Elimination, transformed cells are destroyed by a competent immune system. Sporadic tumour cells that manage to survive immune destruction may then enter an Equilibrium phase where editing occurs. The Escape phase represents the third and final phase of the process, where immunologically sculpted tumours begin to grow progressively, become clinically apparent and establish an immunosuppressive tumour microenvironment. This review focuses on important recent developments that have enhanced our understanding of each phase of the cancer Immunoediting process, summarizes the discovery of new predictive and prognostic biomarkers and discusses development of novel and objectively effective cancer immunotherapies.
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New insights into cancer Immunoediting and its three component phases — elimination, equilibrium and escape
Current opinion in immunology, 2014Co-Authors: Deepak Mittal, Robert D. Schreiber, Matthew M. Gubin, Mark J. SmythAbstract:The principles of cancer Immunoediting have set the foundations for understanding the dual host-protective and tumour sculpting actions of immunity on cancer and establishing the basis for novel individualized cancer immunotherapies. During cancer Immunoediting, the host immune system shapes tumour fate in three phases through the activation of innate and adaptive immune mechanisms. In the first phase, Elimination, transformed cells are destroyed by a competent immune system. Sporadic tumour cells that manage to survive immune destruction may then enter an Equilibrium phase where editing occurs. The Escape phase represents the third and final phase of the process, where immunologically sculpted tumours begin to grow progressively, become clinically apparent and establish an immunosuppressive tumour microenvironment. This review focuses on important recent developments that have enhanced our understanding of each phase of the cancer Immunoediting process, summarizes the discovery of new predictive and prognostic biomarkers and discusses development of novel and objectively effective cancer immunotherapies.
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Cancer Immunoediting: antigens, mechanisms, and implications to cancer immunotherapy
Annals of the New York Academy of Sciences, 2013Co-Authors: Matthew D Vesely, Robert D. SchreiberAbstract:Accumulated data from animal models and human cancer patients strongly support the concept that the immune system can identify and control nascent tumor cells in a process called cancer immunosurveillance. In addition, the immune system can also promote tumor progression through chronic inflammation, immunoselection of poorly immunogenic variants, and suppressing antitumor immunity. Together, the dual host-protective and tumor-promoting actions of immunity are referred to as cancer Immunoediting. The current framework of cancer Immunoediting is a dynamic process comprised of three distinct phases: elimination, equilibrium, and escape. Recently, we demonstrated that immunoselection by CD8(+) T cells of tumor variants lacking strong tumor-specific antigens represents one mechanism by which cancer cells escape tumor immunity and points toward the future of personalized cancer therapy.
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Abstract IA2: The molecular basis of tumor immunogenicity.
Tumor Microenvironment, 2013Co-Authors: Robert D. SchreiberAbstract:Cancer Immunoediting is the process by which the immune system controls and shapes cancer. We originally envisaged that cancer Immunoediting would occur in three phases: Elimination (also known as cancer immunosurveillance, the host protective phase of the process), Equilibrium (the phase in which tumor cells that survive immune elimination remain under immunologic growth control resulting in a state of functional tumor dormancy) and Escape (the phase where clinically apparent tumors emerge because immune sculpting of the tumor cells has produced variants that display either reduced immunogenicity or enhanced immunosuppressive activity). Strong experimental data has now been obtained using mouse models of cancer to demonstrate the existence of each phase of the cancer Immunoediting process and compelling clinical data suggests that a similar process may also occur during the evolution of certain types of human cancer. Our efforts now focus on elucidating the molecular and cellular mechanisms that underlie each phase of cancer Immunoediting and identifying the critical checkpoints that regulate progression from one phase of the process to the next. This approach has helped identify the nature of antigens seen by immunity in nascent developing cancers and has further shown that immunoselection is a major mechanism of Immunoediting. Moreover, we have found that edited tumors can still be controlled by the immune system if natural mechanisms that prevent autoimmunity are suspended. As reported by others, we have confirmed that inhibition of CTLA-4 induces ejection of edited MCA sarcomas. However, we have also found that inhibition of PD-L1 does the same, although by perhaps different mechanisms. These differences will be discussed. Citation Format: Robert D. Schreiber. The molecular basis of tumor immunogenicity. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology: Multidisciplinary Science Driving Basic and Clinical Advances; Dec 2-5, 2012; Miami, FL. Philadelphia (PA): AACR; Cancer Res 2013;73(1 Suppl):Abstract nr IA2.
Gavin P Dunn - One of the best experts on this subject based on the ideXlab platform.
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Therapeutic Applications of the Cancer Immunoediting Hypothesis.
Seminars in cancer biology, 2021Co-Authors: Rupen Desai, Andrew T. Coxon, Gavin P DunnAbstract:Abstract Since the late 19th century, the immune system has increasingly garnered interest as a novel avenue for cancer therapy, particularly given scientific breakthroughs in recent decades delineating the fundamental role of the immune system in tumorigenesis. The Immunoediting hypothesis has articulated this role, describing three phases of the tumor-immune system interaction: Elimination, Equilibrium, and Escape wherein tumors progress from active immunologic surveillance and destruction through dynamic immunologic stasis to unfettered growth. The primary goals of immunotherapy are to restrict and revert progression through these phases, thereby improving the immune system’s ability to control tumor growth. In this review, we detail the development and foundation of the cancer Immunoediting hypothesis and apply this hypothesis to the dynamic immunotherapy field that includes checkpoint blockade, vaccine therapy, and adoptive cell transfer.
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Cancer Immunoediting in malignant glioma.
Neurosurgery, 2012Co-Authors: Gavin P Dunn, Peter E. Fecci, William T. CurryAbstract:Significant work from many laboratories over the last decade in the study of cancer immunology has resulted in the development of the cancer Immunoediting hypothesis. This contemporary framework of the naturally arising immune system-tumor interaction is thought to comprise 3 phases: elimination, wherein immunity subserves an extrinsic tumor suppressor function and destroys nascent tumor cells; equilibrium, wherein tumor cells are constrained in a period of latency under immune control; and escape, wherein tumor cells outpace immunity and progress clinically. In this review, we address in detail the relevance of the cancer Immunoediting concept to neurosurgeons and neuro-oncologists treating and studying malignant glioma by exploring the de novo immune response to these tumors, how these tumors may persist in vivo, the mechanisms by which these cells may escape/attenuate immunity, and ultimately how this concept may influence our immunotherapeutic approaches.
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type i interferon is selectively required by dendritic cells for immune rejection of tumors
Journal of Experimental Medicine, 2011Co-Authors: Mark S Diamond, Gavin P Dunn, Michael J White, Michelle Kinder, Hirokazu Matsushita, Mona Mashayekhi, Jessica M Archambault, Hsiaoju Lee, Cora D Arthur, Ulrich KalinkeAbstract:Cancer Immunoediting is the process whereby the immune system suppresses neoplastic growth and shapes tumor immunogenicity. We previously reported that type I interferon (IFN-α/β) plays a central role in this process and that hematopoietic cells represent critical targets of type I IFN’s actions. However, the specific cells affected by IFN-α/β and the functional processes that type I IFN induces remain undefined. Herein, we show that type I IFN is required to initiate the antitumor response and that its actions are temporally distinct from IFN-γ during cancer Immunoediting. Using mixed bone marrow chimeric mice, we demonstrate that type I IFN sensitivity selectively within the innate immune compartment is essential for tumor-specific T cell priming and tumor elimination. We further show that mice lacking IFNAR1 (IFN-α/β receptor 1) in dendritic cells (DCs; Itgax-Cre+Ifnar1f/f mice) cannot reject highly immunogenic tumor cells and that CD8α+ DCs from these mice display defects in antigen cross-presentation to CD8+ T cells. In contrast, mice depleted of NK cells or mice that lack IFNAR1 in granulocytes and macrophage populations reject these tumors normally. Thus, DCs and specifically CD8α+ DCs are functionally relevant targets of endogenous type I IFN during lymphocyte-mediated tumor rejection.
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interferons immunity and cancer Immunoediting
Nature Reviews Immunology, 2006Co-Authors: Gavin P Dunn, Catherine M Koebel, Robert D. SchreiberAbstract:A clear picture of the dynamic relationship between the host immune system and cancer is emerging as the cells and molecules that participate in naturally occurring antitumour immune responses are being identified. The interferons (IFNs) - that is, the type I IFNs (IFNalpha and IFNbeta) and type II IFN (IFNgamma) - have emerged as central coordinators of tumour-immune-system interactions. Indeed, the decade-old finding that IFNgamma has a pivotal role in promoting antitumour responses became the focus for a renewed interest in the largely abandoned concept of cancer immunosurveillance. More recently, type I IFNs have been found to have distinct functions in this process. In this Review, we discuss the roles of the IFNs, not only in cancer immunosurveillance but also in the broader process of cancer Immunoediting.
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A critical function for type I interferons in cancer Immunoediting
Nature immunology, 2005Co-Authors: Gavin P Dunn, Mark S Diamond, Cora D Arthur, Catherine M Koebel, Jack D. Bui, Ravindra Uppaluri, Allen T Bruce, Kathleen C F Sheehan, Vijay Shankaran, J Michael WhiteAbstract:'Cancer Immunoediting' is a process wherein the immune system protects hosts against tumor development and facilitates outgrowth of tumors with reduced immunogenicity. Although interferon-γ (IFN-γ) is known to be involved in this process, the involvement of type I interferons (IFN-α/β) has not been elucidated. We now show that, like IFN-γ, endogenously produced IFN-α/β was required for the prevention of the growth of primary carcinogen–induced and transplantable tumors. Although tumor cells are important IFN-γ targets, they are not functionally relevant sites of the actions of the type I interferons. Instead, host hematopoietic cells are critical IFN-α/β targets during development of protective antitumor responses. Therefore, type I interferons are important components of the cancer Immunoediting process and function in a way that does not completely overlap the functions of IFN-γ.
Anne Krogsdam - One of the best experts on this subject based on the ideXlab platform.
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Targeting immune checkpoints potentiates Immunoediting and changes the dynamics of tumor evolution.
Nature communications, 2018Co-Authors: Mirjana Efremova, Victoria Klepsch, Pornpimol Charoentong, Francesca Finotello, Dietmar Rieder, Hubert Hackl, Gottfried Baier, Natascha Hermann-kleiter, Martin Löwer, Anne KrogsdamAbstract:The cancer Immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the tumor by editing its genome. Here, we elucidate the impact of evolutionary and immune-related forces on editing the tumor in a mouse model for hypermutated and microsatellite-instable colorectal cancer. Analyses of wild-type and immunodeficient RAG1 knockout mice transplanted with MC38 cells reveal that upregulation of checkpoint molecules and infiltration by Tregs are the major tumor escape mechanisms. Our results show that the effects of Immunoediting are weak and that neutral accumulation of mutations dominates. Targeting the PD-1/PD-L1 pathway using immune checkpoint blocker effectively potentiates Immunoediting. The Immunoediting effects are less pronounced in the CT26 cell line, a non-hypermutated/microsatellite-instable model. Our study demonstrates that neutral evolution is another force that contributes to sculpting the tumor and that checkpoint blockade effectively enforces T-cell-dependent immunoselective pressure.
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Targeting immune checkpoints potentiates Immunoediting and changes the dynamics of tumor evolution
Nature Publishing Group, 2018Co-Authors: Mirjana Efremova, Victoria Klepsch, Pornpimol Charoentong, Francesca Finotello, Dietmar Rieder, Hubert Hackl, Gottfried Baier, Natascha Hermann-kleiter, Martin Löwer, Anne KrogsdamAbstract:The cancer Immunoediting hypothesis assumes the immune system sculpts the cancer genome. Here the authors show, in a mouse model, that neutral evolution outweighs the effects of immunoselection and that immune checkpoint blockade potentiates the Immunoediting, switching the system to non-neutral evolution
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targeting the pd 1 pd l1 pathway potentiates Immunoediting and changes the dynamics of neutral evolution in a mouse model of colorectal cancer
bioRxiv, 2017Co-Authors: Mirjana Efremova, Victoria Klepsch, Pornpimol Charoentong, Francesca Finotello, Dietmar Rieder, Hubert Hackl, Natascha Hermannkleiter, Martin Loewer, Gottfried Baier, Anne KrogsdamAbstract:The cancer Immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the tumor by editing the genome. However, to what extent Immunoediting is shaping the cancer genome is still a matter of debate. Moreover, the impact of cancer immunotherapy with checkpoint blockers on modulating Immunoediting remains largely unexplored. Here we elucidated the impact of evolutionary and immune-related forces on editing the tumor in a mouse model of colorectal cancer (CRC). We first show that MC38 cell line is a valid model for hypermutated and microsatellite-unstable (MSI) CRC. Analyses of longitudinal samples of wild type and immunodeficient RAG1 knockout mice transplanted with MC38 cells revealed that upregulation of checkpoint molecules and infiltration of Tregs are the major tumor escape mechanisms. Strikingly, the impact of neutral evolution on sculpting the tumor outweighed Immunoediting. Targeting the PD-1/PD-L1 pathway potentiated Immunoediting and rendered tumors more homogeneous in the MC38 model. The Immunoediting effects were less pronounced in a nonhypermutated/MSI- model CT26. Our study demonstrates that neutral evolution is the major force that sculpts the tumor, and that checkpoint blockade effectively enforces T cell dependent immunoselective pressure in a hypermutated/MSI model of CRC.
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Targeting the PD-1/PD-L1 pathway potentiates Immunoediting to counterbalance neutral evolution in a mouse model of colorectal cancer
2017Co-Authors: Zlatko Trajanoski, Mirjana Efremova, Victoria Klepsch, Pornpimol Charoentong, Francesca Finotello, Dietmar Rieder, Hubert Hackl, Gottfried Baier, Natascha Hermann-kleiter, Anne KrogsdamAbstract:Background: The cancer Immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the developing tumor by editing the cancer genome. However, to what extent Immunoediting is shaping the cancer genome in common malignancies is still a matter of debate. Moreover, the impact of cancer immunotherapy with checkpoint blockers on modulating Immunoediting remains largely unexplored. Results: Here we employed a mouse model of colorectal cancer (CRC), next-generation sequencing, and computational analyses to elucidate the impact of evolutionary and immune-related forces on editing the tumor. We first carried out genomic and transcriptomic analyses of a widely-used model, MC38 cell line and show that this is a valid model for hypermutated and microsatellite-unstable CRC. Analyses of the data from longitudinal samples of wild type and immunodeficient RAG1 knockout mice transplanted with MC38 cells revealed that upregulation of checkpoint molecules and infiltration of Tregs are the major tumor escape mechanisms. Strikingly, the impact of neutral evolution on sculpting the tumor outweighed Immunoediting by T cell dependent and T cell independent mechanisms in the progressing tumors. We also show that targeting the PD-1/PD-L1 pathway potentiated Immunoediting and rendered tumors more homogeneous. Conclusions: In summary, our study demonstrates that neutral evolution is the major force that sculpts the tumor during progression, and that checkpoint blockade effectively enforces T cell dependent immunoselective pressure in this model. The results have important implication for basic research studies on the mechanisms of resistance to checkpoint blockade and for clinical translation.
Mirjana Efremova - One of the best experts on this subject based on the ideXlab platform.
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Targeting immune checkpoints potentiates Immunoediting and changes the dynamics of tumor evolution.
Nature communications, 2018Co-Authors: Mirjana Efremova, Victoria Klepsch, Pornpimol Charoentong, Francesca Finotello, Dietmar Rieder, Hubert Hackl, Gottfried Baier, Natascha Hermann-kleiter, Martin Löwer, Anne KrogsdamAbstract:The cancer Immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the tumor by editing its genome. Here, we elucidate the impact of evolutionary and immune-related forces on editing the tumor in a mouse model for hypermutated and microsatellite-instable colorectal cancer. Analyses of wild-type and immunodeficient RAG1 knockout mice transplanted with MC38 cells reveal that upregulation of checkpoint molecules and infiltration by Tregs are the major tumor escape mechanisms. Our results show that the effects of Immunoediting are weak and that neutral accumulation of mutations dominates. Targeting the PD-1/PD-L1 pathway using immune checkpoint blocker effectively potentiates Immunoediting. The Immunoediting effects are less pronounced in the CT26 cell line, a non-hypermutated/microsatellite-instable model. Our study demonstrates that neutral evolution is another force that contributes to sculpting the tumor and that checkpoint blockade effectively enforces T-cell-dependent immunoselective pressure.
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Targeting immune checkpoints potentiates Immunoediting and changes the dynamics of tumor evolution
Nature Publishing Group, 2018Co-Authors: Mirjana Efremova, Victoria Klepsch, Pornpimol Charoentong, Francesca Finotello, Dietmar Rieder, Hubert Hackl, Gottfried Baier, Natascha Hermann-kleiter, Martin Löwer, Anne KrogsdamAbstract:The cancer Immunoediting hypothesis assumes the immune system sculpts the cancer genome. Here the authors show, in a mouse model, that neutral evolution outweighs the effects of immunoselection and that immune checkpoint blockade potentiates the Immunoediting, switching the system to non-neutral evolution
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targeting the pd 1 pd l1 pathway potentiates Immunoediting and changes the dynamics of neutral evolution in a mouse model of colorectal cancer
bioRxiv, 2017Co-Authors: Mirjana Efremova, Victoria Klepsch, Pornpimol Charoentong, Francesca Finotello, Dietmar Rieder, Hubert Hackl, Natascha Hermannkleiter, Martin Loewer, Gottfried Baier, Anne KrogsdamAbstract:The cancer Immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the tumor by editing the genome. However, to what extent Immunoediting is shaping the cancer genome is still a matter of debate. Moreover, the impact of cancer immunotherapy with checkpoint blockers on modulating Immunoediting remains largely unexplored. Here we elucidated the impact of evolutionary and immune-related forces on editing the tumor in a mouse model of colorectal cancer (CRC). We first show that MC38 cell line is a valid model for hypermutated and microsatellite-unstable (MSI) CRC. Analyses of longitudinal samples of wild type and immunodeficient RAG1 knockout mice transplanted with MC38 cells revealed that upregulation of checkpoint molecules and infiltration of Tregs are the major tumor escape mechanisms. Strikingly, the impact of neutral evolution on sculpting the tumor outweighed Immunoediting. Targeting the PD-1/PD-L1 pathway potentiated Immunoediting and rendered tumors more homogeneous in the MC38 model. The Immunoediting effects were less pronounced in a nonhypermutated/MSI- model CT26. Our study demonstrates that neutral evolution is the major force that sculpts the tumor, and that checkpoint blockade effectively enforces T cell dependent immunoselective pressure in a hypermutated/MSI model of CRC.
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Targeting the PD-1/PD-L1 pathway potentiates Immunoediting to counterbalance neutral evolution in a mouse model of colorectal cancer
2017Co-Authors: Zlatko Trajanoski, Mirjana Efremova, Victoria Klepsch, Pornpimol Charoentong, Francesca Finotello, Dietmar Rieder, Hubert Hackl, Gottfried Baier, Natascha Hermann-kleiter, Anne KrogsdamAbstract:Background: The cancer Immunoediting hypothesis postulates a dual role of the immune system: protecting the host by eliminating tumor cells, and shaping the developing tumor by editing the cancer genome. However, to what extent Immunoediting is shaping the cancer genome in common malignancies is still a matter of debate. Moreover, the impact of cancer immunotherapy with checkpoint blockers on modulating Immunoediting remains largely unexplored. Results: Here we employed a mouse model of colorectal cancer (CRC), next-generation sequencing, and computational analyses to elucidate the impact of evolutionary and immune-related forces on editing the tumor. We first carried out genomic and transcriptomic analyses of a widely-used model, MC38 cell line and show that this is a valid model for hypermutated and microsatellite-unstable CRC. Analyses of the data from longitudinal samples of wild type and immunodeficient RAG1 knockout mice transplanted with MC38 cells revealed that upregulation of checkpoint molecules and infiltration of Tregs are the major tumor escape mechanisms. Strikingly, the impact of neutral evolution on sculpting the tumor outweighed Immunoediting by T cell dependent and T cell independent mechanisms in the progressing tumors. We also show that targeting the PD-1/PD-L1 pathway potentiated Immunoediting and rendered tumors more homogeneous. Conclusions: In summary, our study demonstrates that neutral evolution is the major force that sculpts the tumor during progression, and that checkpoint blockade effectively enforces T cell dependent immunoselective pressure in this model. The results have important implication for basic research studies on the mechanisms of resistance to checkpoint blockade and for clinical translation.
