Lee, Claudia Shi Ya; (2023) Microenvironment-mediated immune evasion in primary non-small cell lung cancer. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Immune checkpoint inhibitor therapy holds therapeutic promise for patients with cancer. Yet, its efficacy is hindered by immune evasion and intratumour heterogeneity. Disruption to antigen presentation pathways is a well-studied cancer cell-intrinsic mechanism of evading immune predation, however, its interplay with the geographical arrangement and heterogeneity of the immune tumour microenvironment is not fully understood. In my thesis, I analysed spatial data derived from imaging mass cytometry of the immune tumour microenvironment and integrated paired genomic information from patients with non-small cell lung cancer in the TRACERx cohort. First, I characterised the spatial microenvironment landscape, with a focus on the organisation of recurrently co-localising cells, termed spatial cellular communities, in tumour and adjacent normal tissue. I also quantified microenvironment heterogeneity in non-small cell lung cancer. Next, I studied spatial cellular communities in the context of immune evasion in cancer. Highly immune infiltrated microenvironments consisting of CD8 T cells and immunosuppressive CD163+CD206+ macrophages organised into spatial communities. The abundance of these spatial hubs correlated with clonal neoantigen burden in lung invasive adenocarcinoma. Moreover, I found evidence that, in the absence of antigen presentation disruption, the spatial interactions between CD8 T cells and CD163+CD206+ macrophages may mediate immune evasion. This microenvironment spatial phenotype was associated with poorer disease-free survival in the TRACERx cohort (n = 63 patients). Finally, I identified low intratumour heterogeneity targets to inform immune checkpoint molecule inhibition strategies. Beyond T cells, I catalogued the expression of immune checkpoint molecules in B cell lineage and myeloid cell populations. TIM-3 and LAG-3, two actionable immune checkpoint molecules on CD8 T cells, CD163+CD206+ macrophages and plasma cells, displayed low intratumour heterogeneity and may be promising therapeutic targets. In summary, this work provides insight into the spatial architecture of non-small cell lung cancer and proposes low intratumour heterogeneity therapeutic targets to address microenvironment-mediated immune evasion.

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