Integrative genomic approaches to dissecting host-tumor and host-pathogen immune processes
Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2015.
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| Format: | Thesis |
| Language: | eng |
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Massachusetts Institute of Technology
2015
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| Online Access: | http://hdl.handle.net/1721.1/98722 |
| _version_ | 1826189924589633536 |
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| author | Rooney, Michael Steven |
| author2 | Nir Hacohen. |
| author_facet | Nir Hacohen. Rooney, Michael Steven |
| author_sort | Rooney, Michael Steven |
| collection | MIT |
| description | Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2015. |
| first_indexed | 2024-09-23T08:30:07Z |
| format | Thesis |
| id | mit-1721.1/98722 |
| institution | Massachusetts Institute of Technology |
| language | eng |
| last_indexed | 2024-09-23T08:30:07Z |
| publishDate | 2015 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/987222019-04-09T18:19:37Z Integrative genomic approaches to dissecting host-tumor and host-pathogen immune processes Rooney, Michael Steven Nir Hacohen. Harvard--MIT Program in Health Sciences and Technology. Harvard--MIT Program in Health Sciences and Technology. Harvard--MIT Program in Health Sciences and Technology. Thesis: Ph. D., Harvard-MIT Program in Health Sciences and Technology, 2015. Cataloged from PDF version of thesis. Includes bibliographical references (pages 243-263). Two parallel research efforts were pursued. First, we conducted a systematic exploration of how the genomic landscape of cancer shapes and is shaped by anti-tumor immunity. Using large-scale genomic data sets of solid tissue tumor biopsies, we quantified the cytolytic activity of the local immune infiltrate and identified associated properties across 18 tumor types. The number of predicted MHC Class I-associated neoantigens was correlated with cytolytic activity and was lower than expected in colorectal and other tumors, suggesting immune-mediated elimination. We identified recurrently mutated genes that showed positive association with cytolytic activity, including beta-2- microglobulin (B2M), HLA-A, -B and -C and Caspase 8 (CASP8), highlighting loss of antigen presentation and blockade of extrinsic apoptosis as key strategies of resistance to cytolytic activity. Genetic amplifications were also associated with high cytolytic activity, including immunosuppressive factors such as PDL1/2 and ALOX12B/15B. Our genetic findings thus provide evidence for immunoediting in tumors and uncover mechanisms of tumor-intrinsic resistance to cytolytic activity. Second, we combined measurements of protein production and degradation and mRNA dynamics so as to build a quantitative genomic model of the differential regulation of gene expression in lipopolysaccharide-stimulated mouse dendritic cells. Changes in mRNA abundance play a dominant role in determining most dynamic fold changes in protein levels. Conversely, the preexisting proteome of proteins performing basic cellular functions is remodeled primarily through changes in protein production or degradation, accounting for more than half of the absolute change in protein molecules in the cell. Thus, the proteome is regulated by transcriptional induction for newly activated cellular functions and by protein lifecycle changes for remodeling of preexisting functions. by Michael Steven Rooney. Ph. D. 2015-09-17T19:07:28Z 2015-09-17T19:07:28Z 2015 2015 Thesis http://hdl.handle.net/1721.1/98722 920869889 eng M.I.T. theses are protected by copyright. They may be viewed from this source for any purpose, but reproduction or distribution in any format is prohibited without written permission. See provided URL for inquiries about permission. http://dspace.mit.edu/handle/1721.1/7582 263 pages application/pdf Massachusetts Institute of Technology |
| spellingShingle | Harvard--MIT Program in Health Sciences and Technology. Rooney, Michael Steven Integrative genomic approaches to dissecting host-tumor and host-pathogen immune processes |
| title | Integrative genomic approaches to dissecting host-tumor and host-pathogen immune processes |
| title_full | Integrative genomic approaches to dissecting host-tumor and host-pathogen immune processes |
| title_fullStr | Integrative genomic approaches to dissecting host-tumor and host-pathogen immune processes |
| title_full_unstemmed | Integrative genomic approaches to dissecting host-tumor and host-pathogen immune processes |
| title_short | Integrative genomic approaches to dissecting host-tumor and host-pathogen immune processes |
| title_sort | integrative genomic approaches to dissecting host tumor and host pathogen immune processes |
| topic | Harvard--MIT Program in Health Sciences and Technology. |
| url | http://hdl.handle.net/1721.1/98722 |
| work_keys_str_mv | AT rooneymichaelsteven integrativegenomicapproachestodissectinghosttumorandhostpathogenimmuneprocesses |