The immunobiology of B Lymphocytes in non-small cell lung cancer

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Patel, Akshay Jatin (2023). The immunobiology of B Lymphocytes in non-small cell lung cancer. University of Birmingham. Ph.D.

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Abstract

Lung cancer is the second most diagnosed cancer, after breast cancer, worldwide. However, it is still the leading cause of cancer-specific mortality globally, contributing to 18% of all cancer-related deaths. Non-small cell lung cancer (NSCLC) makes up 85% of lung cancers and dependent on the stage, is amenable to a wide of treatments from surgery to systemic therapy. Immune responses within the tumour microenvironment have increasingly been implicated as determining factors in tumour progression and aggressiveness, and the focus has predominated on T-cell biology. The immune response is a complex interplay between the primary tumour and microenvironment, T and B cells. The role of the B cell in tumour survival is unclear but clearly has a function as tumour infiltration is commonly reported.
Through deep phenotyping and multispectral tissue imaging techniques, we identified key differences in the effector and suppressive B cell composition between the tumour and peripheral blood compartments. IL10 positive suppressive B regulatory phenotypes were significantly more abundant in the circulation of patients who recurred post-operatively. Using a broad spectrum immunome array, we employed machine learning techniques and identified an auto-antibody signature in the serum of NSCLC patients that was highly predictive for post-operative recurrence in two independent cohorts.
In addition to the techniques described above, we utilised functional ex vivo B cell assays to interrogate the response to checkpoint blockade in advanced disease patients and how this relates to B cell dynamics. Our findings demonstrated that lack of a suppressive B cell “brake” predisposed patients to high grade immune related adverse events post-treatment. Moreover, the B cells from toxicity patients were not only functionally defective in their ability to produce IL10 but also displayed a pan cytokine failure affecting pro-inflammatory cytokines thus suggesting B cell exhaustion in these patients. These findings significantly enhanced our understanding of the aetiopathogenesis of auto-immune toxicity secondary to checkpoint blockade with anti PD-1/PDL-1.
In summary, this study aimed to explore the role of B cell biology in NSCLC by employing deep phenotyping and functional assay techniques at the blood and tissue level in both early and advanced stage disease. Our findings are likely to be informative in biomarker development for predicting response to treatment, post-operative relapse and for therapeutic adjuvant polyepitopic vaccine strategies in high-risk patients.

Type of Work:

Thesis (Doctorates > Ph.D.)

Award Type:

Doctorates > Ph.D.

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