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Tumor Intrinsic Factors Shape the Tumor Immune Microenvironment

CHEN, XUEER (2021) Tumor Intrinsic Factors Shape the Tumor Immune Microenvironment. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Studying tumor microenvironment would benefit our understanding of the immune escape mechanisms. Tumor somatic genome alterations (SGAs) as potential intrinsic factors can regulate tumor micro-environment. Tumor-specific causal inference (TCI) is a Bayesian structure learning method that identifies driver SGAs for differentially expressed genes in individual tumors. We applied the TCI algorithm to systematically search for SGA events that causally regulated expression of genes involved in immune responses. This lead to a comprehensive profile of immune-modulating SGAs that serve as causes of immune evasion in tumors, as well as potential signaling pathways perturbed by such SGAs. Basically, although different tumors present heterogeneity in selection of SGAs (tumors of the same cancer type usually have distinct sets of SGAs), they may share similar immune evasion mechanisms (studies have identified tumor subtypes with similar immune infiltration profiles). Building systematic models between SGAs and immune profiles would help identifying signaling pathways which are composed of SGAs leading to the similar immune profiles, thus providing treatable targets for patients of distinct SGAs.
Modeling the potential interaction and causal relationships among the multiple cell (sub)types/states helps in understanding intercellular communication. Single cell RNA-sequencing (scRNA-seq) technology is becoming crucial for studying the tumor micro-environment at the cellular level. We adopted topic modeling to learn stable and novel cell types/states in scRNA-seq data. Considering the number of patients studied in most of current scRNA-seq studies (usually <30), to increase the statistical power of the study of interactions among cells, we applied appropriate methods to infer the cell types/states identified from scRNA-seq data in bulk tumor tissue RNA-seq data (e.g., The Cancer Genome Atlas data), and we then searched for potential causal relations among stromal and immune cells within the tumor micro-environment in more than hundreds of patients. The results provide support that the cellular states of diverse cells were coordinated through intercellular communication networks.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
CHEN, XUEERxuc10@pitt.eduxuc10
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairCooper, Gregorygfc@pitt.edu
Committee CoChairLu, Xinghuaxinghua@pitt.edu
Committee MemberLu, Binfengbinfeng@pitt.edu
Committee MemberLu, Songjiansongjian@pitt.edu
Date: 6 January 2021
Date Type: Publication
Defense Date: 1 December 2020
Approval Date: 6 January 2021
Submission Date: 10 December 2020
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 150
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Biomedical Informatics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: tumor microenvironment, somatic gene alteration, intrinsic factor, immunology, single cell
Date Deposited: 06 Jan 2021 19:54
Last Modified: 06 Jan 2021 19:54
URI: http://d-scholarship.pitt.edu/id/eprint/39966

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