The role of the immune microenvironment in mesothelioma and lung cancer

Graef, Suzanne (2020). The role of the immune microenvironment in mesothelioma and lung cancer. University of Birmingham. Ph.D.

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Abstract

Mesothelioma develops on a background of chronic inflammation, promoting a cytokine rich environment which can alter the profile and function of the immune system. Immunomodulatory treatments have transformed prognosis of many cancers, while mesothelioma outcomes remain poor. Understanding the immunobiology of mesothelioma may unlock resistance and drive progress.

The immune microenvironment of mesothelioma and NSCLC were examined to determine whether T cell immunity could be impaired through myeloid induced T cell tolerance and direct tumour and T cell interactions. Evaluation of peripheral blood and tumour specimens revealed abnormal blood profiles, with high percentages of CD15 and CD14 positive cells and reduced T cell percentages. Mesothelioma tumour cells allowed assessment of the cytokine profile, demonstrating that GM-CSF induced production of reactive oxygen species by granulocytes, leading to T cell inactivation. T cell and dendritic cell dysfunction were also directly induced by mesothelioma, driven by induction of STAT3, as demonstrated by partial rescue with AZD9150.

Sequential peripheral blood profiles were assessed in MATRIX and PEPS2 clinical trials of checkpoint inhibition in NSCLC. A high neutrophil-to-lymphocyte ratio was significantly predictive of poorer outcome, specifically following the first cycle of treatment. These findings support the theory that immune competence is required for optimal response to immunomodulatory treatments.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

Supervisor(s):