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Arlene Sharpe. Juneja, Vikram R Harvard--MIT Program in Health Sciences and Technology. Harvard University--MIT Division of Health Sciences and Technology 2017-05-11T19:58:01Z 2017-05-11T19:58:01Z 2017 2017 http://hdl.handle.net/1721.1/108961 986488635 Thesis: Ph. D. in Medical Engineering and Medical Physics, Harvard-MIT Program in Health Sciences and Technology, 2017. Cataloged from PDF version of thesis. Includes bibliographical references (pages 164-176). The immune system has proven valuable in the fight against cancer. Therapies that unleash a T cell response against tumors have led to durable remissions in multiple cancers. Specifically, antibodies blocking the programmed death (PD)-1 pathway have been approved for the treatment of metastatic melanoma, non-small cell lung cancer, and renal cell carcinoma, amongst others. However, only a limited number of patients respond to these therapies. The field is now trying to determine combination strategies and biomarkers to extend the benefits of these therapies to additional patients in a rationale manner. A fundamental challenge towards this goal is that the cellular and molecular mechanisms underlying the efficacy of PD-1 pathway blockade are not well understood. In this thesis, we dissected the role of PD-1 and its ligands on multiple cell types in the tumor microenvironment. PD-1 is a receptor expressed on T cells upon activation, amongst other cells. Its ligands, PD-L1 and PD-L2, can be expressed on many cell types, including tumor cells. In the first section, we show that PD-1 pathway blockade can effectively combine with another therapy targeted at tumor cells themselves, BRAF inhibitors. This work provided support for ongoing clinical trials. In the second section, we show that tumor cells can protect themselves from immune eradication by expressing PD-L1, which directly suppresses the cytotoxicity of CD8* T cells. This establishes a key mechanism by which the PD-1 pathway prevents effective antitumor immunity. In the third section, we show that the inhibition of CD8* T cell cytotoxicity through PD-1 signaling is due in part to cell-intrinsic and cell-extrinsic suppression of T cell metabolism. Removing the inhibitory PD-1 signal on a fraction of cells enhances their metabolic state and allows them to become more cytotoxic. In turn, this creates a tumor microenvironment that allows additional CD8* T cells to become more functional. We show that pharmacologic agents that mimic these effects of metabolism can enhance CD8* T cell cytotoxicity. These mechanistic insights will assist in developing cancer therapies that combine PD-1 blockade with other approaches to broaden the benefit of PD-1 immunotherapy. by Vikram R. Juneja. Ph.D. in Medical Engineering and Medical Physics 190 pages eng Massachusetts Institute of Technology MIT theses are protected by copyright. They may be viewed, downloaded, or printed from this source but further reproduction or distribution in any format is prohibited without written permission. http://dspace.mit.edu/handle/1721.1/7582 Harvard--MIT Program in Health Sciences and Technology. The role of the PD-1 pathway in the tumor microenvironment Role of the programmed death-one pathway in the tumor microenvironment Thesis application/pdf false Publication unknown unknown <Publication xmlns="https://www.openaire.eu/cerif-profile/1.1/" id="87cfda8d-7902-4053-99e1-cb9f281978e4"> <Type xmlns="https://www.openaire.eu/cerif-profile/vocab/COAR_Publication_Types">http://purl.org/coar/resource_type/c_1843</Type> <Language>eng</Language> <Title>The role of the PD-1 pathway in the tumor microenvironment</Title> <Subtitle>Role of the programmed death-one pathway in the tumor microenvironment</Subtitle> <PublishedIn> <Publication> </Publication> </PublishedIn> <PublicationDate>2017</PublicationDate> <Authors> <Author> <DisplayName>Juneja, Vikram R</DisplayName> <Affiliation> <OrgUnit> </OrgUnit> </Affiliation> </Author> </Authors> <Editors> </Editors> <Publishers> <Publisher> <DisplayName>Massachusetts Institute of Technology</DisplayName> <OrgUnit /> </Publisher> </Publishers> <License>http://dspace.mit.edu/handle/1721.1/7582</License> <Keyword>Harvard--MIT Program in Health Sciences and Technology.</Keyword> <Abstract>The immune system has proven valuable in the fight against cancer. Therapies that unleash a T cell response against tumors have led to durable remissions in multiple cancers. Specifically, antibodies blocking the programmed death (PD)-1 pathway have been approved for the treatment of metastatic melanoma, non-small cell lung cancer, and renal cell carcinoma, amongst others. However, only a limited number of patients respond to these therapies. The field is now trying to determine combination strategies and biomarkers to extend the benefits of these therapies to additional patients in a rationale manner. A fundamental challenge towards this goal is that the cellular and molecular mechanisms underlying the efficacy of PD-1 pathway blockade are not well understood. In this thesis, we dissected the role of PD-1 and its ligands on multiple cell types in the tumor microenvironment. PD-1 is a receptor expressed on T cells upon activation, amongst other cells. Its ligands, PD-L1 and PD-L2, can be expressed on many cell types, including tumor cells. In the first section, we show that PD-1 pathway blockade can effectively combine with another therapy targeted at tumor cells themselves, BRAF inhibitors. This work provided support for ongoing clinical trials. In the second section, we show that tumor cells can protect themselves from immune eradication by expressing PD-L1, which directly suppresses the cytotoxicity of CD8* T cells. This establishes a key mechanism by which the PD-1 pathway prevents effective antitumor immunity. In the third section, we show that the inhibition of CD8* T cell cytotoxicity through PD-1 signaling is due in part to cell-intrinsic and cell-extrinsic suppression of T cell metabolism. Removing the inhibitory PD-1 signal on a fraction of cells enhances their metabolic state and allows them to become more cytotoxic. In turn, this creates a tumor microenvironment that allows additional CD8* T cells to become more functional. We show that pharmacologic agents that mimic these effects of metabolism can enhance CD8* T cell cytotoxicity. These mechanistic insights will assist in developing cancer therapies that combine PD-1 blockade with other approaches to broaden the benefit of PD-1 immunotherapy.</Abstract> <Access xmlns="http://purl.org/coar/access_right" > </Access> </Publication>