Microenvironment-mediated immune evasion in primary non-small cell lung cancer
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.
https://discovery.ucl.ac.uk/id/eprint/10182798/1/leec_thesis_corrections.pdf