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Understanding the effects of Myc on lung cancer immune signaling in vitro and in vivo

Kindl, Franziska (2022) MOBN03 20221
Degree Projects in Molecular Biology
Popular Abstract
Understanding the effect of Myc on lung cancer immune signalling in vitro and in vivo

Immune checkpoint blockade therapy (ICBT) is a promising treatment option that is commonly used for advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors targeting the PD-1/PD-L1 interaction have demonstrated remarkable effects. Blocking the PD-1/PD-L1 axis restores tumor cell recognition and secretion of cytokines and, thus, the ability to destroy tumor cells. However, only a subset of NSCLC patients shows a response to this treatment. Resistance to ICBT is often associated with low T cell infiltration and aberrant expression of oncogenes. MYC is one of these genes commonly found in tumors that evade immune surveillance. Thus, it... (More)
Understanding the effect of Myc on lung cancer immune signalling in vitro and in vivo

Immune checkpoint blockade therapy (ICBT) is a promising treatment option that is commonly used for advanced non-small cell lung cancer (NSCLC). Immune checkpoint inhibitors targeting the PD-1/PD-L1 interaction have demonstrated remarkable effects. Blocking the PD-1/PD-L1 axis restores tumor cell recognition and secretion of cytokines and, thus, the ability to destroy tumor cells. However, only a subset of NSCLC patients shows a response to this treatment. Resistance to ICBT is often associated with low T cell infiltration and aberrant expression of oncogenes. MYC is one of these genes commonly found in tumors that evade immune surveillance. Thus, it might be a major driver of resistance to ICBT in NSCLC. MYC is a multifunctional proto-oncogenic protein playing a role in proliferation, metabolism and apoptosis.

The project aimed to get a better understanding of the molecular mechanisms that lead to Myc-induced immune evasion. Further, we tried to find ways of overcoming the immune surveillance of Myc overexpressing lung tumors. First, the in vitro effects of Myc on cell proliferation were studied in MYC overexpression and knockdown murine lung carcinoma models. The obtained growth curves revealed that the proliferation rate of the cells correlated with the Myc abundance. Survival assays were performed to observe the impact of direct and indirect Myc inhibition on the survival ability of Myc-amplified and reduced lung cancer cells. Myc-amplified cells showed a better performance upon treatment with an inhibitor targeting Myc expression. In contrast, inhibition of Myc stabilization seemed to have more effect in Myc overexpressing cells. Gene expression analysis by qPCR revealed a possible correlation between Myc and genes associated with lower survival rates in NSCLC.

The effects of stimulation of the immune response were observed in in vivo experiments. Immunocompetent mice were subcutaneously injected with Myc-high and low lung cancer cells. Interestingly, tumors composed of Myc-high cells grew slower when compared with Myc-low cell tumors. A possible explanation for this observation could be that Myc-high tumors proliferate too fast, resulting in a higher mortality rate and, subsequently better recognition of the immune system.
After tumor formation, mice were treated with either DMXXA or a control vehicle. DMXAA is a STING-agonist maintaining the stimulation of immune response. FACS analysis revealed enhanced antitumor immunity characterized by increased T cell number and reduced tumor growth in DMXAA-treated mice. However, only tumor growth of Myc high tumors was suppressed. Myc low tumors showed no antitumor effects despite the tumor immune cell infiltration. It was demonstrated that DMXAA has cell-line specific effects on growth-suppression of murine lung cancers in a syngeneic setting.

Master’s Degree Project in Molecular Biology, 60 credits, 2022
Department of Biology, Lund University


Advisor: Alexander Schramm
Department of Molecular Oncology
University Hospital Essen (Less)
Please use this url to cite or link to this publication:
author
Kindl, Franziska
supervisor
organization
course
MOBN03 20221
year
type
H2 - Master's Degree (Two Years)
subject
language
English
id
9113595
date added to LUP
2023-04-18 14:44:42
date last changed
2023-04-18 14:44:42
@misc{9113595,
  author       = {{Kindl, Franziska}},
  language     = {{eng}},
  note         = {{Student Paper}},
  title        = {{Understanding the effects of Myc on lung cancer immune signaling in vitro and in vivo}},
  year         = {{2022}},
}