Universität zu Köln

Cai, Jiali (2024). The effect of prescription dose and dose fractionation on the abscopal effect in a mouse model of non-small cell lung cancer. PhD thesis, Universität zu Köln.

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Abstract

Lung cancer is one of the most prevalent and deadliest malignant tumors worldwide, with non-small cell lung cancer being the most common subtype. Besides surgery and chemotherapy, radiotherapy has become one of the fundamental approaches for lung cancer treatment, with approximately 60%–70% of patients requiring it. Radiotherapy has become indispensable, particularly for tumors that are difficult to access, invade critical functional areas, or cannot be surgically removed. Non-small cell lung cancer has a relatively high rate of distant metastasis (around 57%), and radiotherapy can induce direct tumor cell death, promote tumor necrosis, release tumor antigens, and activate the immune system, thereby altering the tumor microenvironment and promoting antitumor immunity. The observation of the abscopal effect in some cases suggests that radiotherapy has a systemic antitumor effect in addition to its local therapeutic effect. The combination of immune checkpoint inhibitors with radiotherapy has been demonstrated to cause the abscopal effect as well. However, the mechanism remains unclear, and suitable animal models for studying the abscopal effect are lacking, emphasizing the need for animal models to better understand this phenomenon, which holds significant clinical promise. This study established animal models of tumors and metastases by inoculating the NSCLC Genetically Engineered Mouse Model (GEMM) [KrasG12DTp53−/−(KP)] cells into immunocompetent mice flanks and determined specific radiotherapy regimens based on the biologically effective dose (BED) values. Radiotherapy targeted the tumor on one side of the mouse (the primary tumor), followed by PD-1 antibody injection for immunotherapy. Tumor volumes were recorded, and growth curves were obtained. The study employed flow cytometry to examine alterations in leukocytes, CD4+ T cells, CD8+ T cells, and the expression of tumor cell surface antibodies in secondary tumor foci. Compared to control and immunotherapy alone, radiotherapy combined with immunotherapy under the same regimen inhibited the growth of secondary tumors. The 8.7Gyx5F radiotherapy schedule was more effective than the 24Gyx1F schedule when comparing secondary tumor growth. Flow cytometry analysis of the immune microenvironment in secondary tumor tissues showed increased infiltration of leukocytes, CD4+ T cells, and CD8+ T cells, along with increased expression of PD-L1 and EpCAM in mice receiving 8.7Gyx5F radiotherapy combined with PD-1 treatment. Continuous fractionated radiotherapy was more effective than a single dose of radiation in controlling secondary tumors compared to radiotherapy with the same BED. When the radiotherapy regimen was consistent, the combined treatment of radiotherapy and immunotherapy showed better tumor control than radiotherapy alone. Mice in this group exhibited enhanced infiltration of immune cells, indicating antitumor immune activity. This study provides important experimental groundwork for the clinical translation of combined radiotherapy and immunotherapy and offers initial insights into the mechanism of radiation-induced abscopal effects. However, further optimization of experimental protocols and data analysis is needed for a comprehensive assessment of the clinical prospects of this combined treatment strategy.

Item Type:	Thesis (PhD thesis)
Creators:	Creators Email ORCID ORCID Put Code Cai, Jiali jiali.cai_med@outlook.com UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-734701
Date:	2024
Language:	English
Faculty:	Faculty of Medicine
Divisions:	Faculty of Medicine > Strahlentherapie > Klinik und Poliklinik für Strahlentherapie
Subjects:	Medical sciences Medicine
Uncontrolled Keywords:	Keywords Language Radiotherapy English abscopal effect English non-small cell lung cancer English mouse model English
Date of oral exam:	27 September 2023
Referee:	Name Academic Title Niessen, Carien Universitätsprofessorin PhD Herter, Jan Privatdozent Dr. med
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/73470