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Combining Molecular and Cellular App...

Garcia Castillo, Jesse,

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Combining Molecular and Cellular Approaches to Break Down the Walls of Immunosuppression and Increase Precision of Cancer Immunotherapies /

Record Type:	Electronic resources : Monograph/item
Title/Author:	Combining Molecular and Cellular Approaches to Break Down the Walls of Immunosuppression and Increase Precision of Cancer Immunotherapies // Jesse Garcia Castillo.
Author:	Garcia Castillo, Jesse,
Description:	1 electronic resource (141 pages)
Notes:	Source: Dissertations Abstracts International, Volume: 86-09, Section: B.
Contained By:	Dissertations Abstracts International86-09B.
Subject:	Immunology. -
Online resource:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31766094
ISBN:	9798310103122

Combining Molecular and Cellular Approaches to Break Down the Walls of Immunosuppression and Increase Precision of Cancer Immunotherapies /
Garcia Castillo, Jesse,

Combining Molecular and Cellular Approaches to Break Down the Walls of Immunosuppression and Increase Precision of Cancer Immunotherapies /Jesse Garcia Castillo. - 1 electronic resource (141 pages)

Source: Dissertations Abstracts International, Volume: 86-09, Section: B.

Immunotherapies have allowed for treating cancer in ways not possible with pre-existing therapies by taking advantage of an individual's ability to limit cancer by their own immune system. Despite the excitement in immunotherapy, only less than 10% of current patients benefit from immunotherapy highlighting the need to improve current immunotherapies. In addition, many immunotherapies cause secondary effects such as development of systemic autoimmunity that negatively impact patient health. My thesis research is broadly focused on identifying strategies for increasing precision of immunotherapies to potentially overcome the suppressive environment in tumors that have made immunotherapies inefficient for the majority of people and prevent secondary side effects. To do this, I developed a new method to identify and track antigen-specific T cells, developed an anti-cancer therapeutic strategy using Listeria monocytogenes (or Listeria), and studied the resistance mechanisms of a population of tumor-promoting T cells called regulatory T cells (Tregs) to oxidative stress within the tumors.Identifying T cells responsive to cancer, bacteria, and viruses has been an important goal for multiple research groups and companies since these T cells are the main drivers for protection against these agents. The current methods available for detecting these T cells have their limitations such as requiring many of these T cells to be present in samples or high cost of sample processing. We developed a low cost and rapid method for detecting T cells that respond to cancer, bacteria (i.e. Listeria) and viruses (i.e. flu) allowing us to monitor their population dynamics and phenotype in response to common immunotherapies.The second approach for improving immunotherapies came from trying to understand responses to a form of immunotherapy called bacterial immunotherapy. This study was inspired by historical work by a physician named Dr. William Coley in the early 20th century that observed sarcomas clear from patients when they developed an infection. This work eventually opened the opportunity to use bacteria to help the immune response against cancer that eventually led to the approval of the first bacteria-based immunotherapy against bladder cancer as well as several clinical trials with the aim to make this type of a therapy a standard of care. We found that Listeria-specific T cells developed from a previous infection was the key difference in determining whether there would be a good immune response against the cancer. Infection in tumor-bearing mice led to the colonization of Listeria in tumors that allowed for the recruitment of neutrophils (PMNs) that were converted into suppressive cells. However, the presence of Listeria-specific T cells allowed for elimination of these infected suppressive neutrophils and promoted an inflammatory tumor microenvironment that allowed for tumor control.The third approach aims at understanding how Tregs respond to oxidative stress in different microenvironments that can potentially lead to identification of pathways to target. We identified that Tregs utilize an additional antioxidant pathway regulated by ferroptosis suppressor protein-1 (FSP1) to limit accumulation of lipid peroxides to promote cell viability and function. Furthermore, this pathway is utilized exclusively by Tregs as tumor control is enhanced in the conditions that FSP1 is knocked out in Tregs specifically or in all T cells. Therefore, FSP1 is a potential target for Tregs that can be utilized to improve cancer immunotherapies where Tregs mediate immunosuppression in the tumor microenvironment.

English

ISBN: 9798310103122Subjects--Topical Terms:

611031
Immunology.
Subjects--Index Terms:

Cancer

Combining Molecular and Cellular Approaches to Break Down the Walls of Immunosuppression and Increase Precision of Cancer Immunotherapies /
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