Microenvironment-mediated immune evasion in primary non-small cell lung cancer - PhDData

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Microenvironment-mediated immune evasion in primary non-small cell lung cancer

The thesis was published by Lee, Claudia Shi Ya, in November 2023, UCL (University College London).

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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