Abstract
Predicting the prognosis of colorectal cancer (CRC) patients remains challenging and a characterisation of the tumour immune environment represents one of the most crucial avenues when attempting to do so. For this reason, molecular approaches which are capable of classifying the immune environments associated with tumour infiltrating lymphocytes (TILs) are being readily investigated. In this proof of concept study, we aim to explore the feasibility of using spatial lipidomics by MALDI-MSI to distinguish CRC tissue based upon their TIL content. Formalin-fixed paraffin-embedded tissue from human thymus and tonsil was first analysed by MALDI-MSI to obtain a curated mass list from a pool of single positive T lymphocytes, whose putative identities were annotated using an LC-MS-based lipidomic approach. A CRC tissue microarray (TMA, n = 30) was then investigated to determine whether these cases could be distinguished based upon their TIL content in the tumour and its microenvironment. MALDI-MSI from the pool of mature T lymphocytes resulted in the generation of a curated mass list containing 18 annotated m/z features. Initially, subsets of T lymphocytes were then distinguished based on their state of maturation and differentiation in the human thymus and tonsil tissue. Then, when applied to a CRC TMA containing differing amounts of T lymphocyte infiltration, those cases with a high TIL content were distinguishable from those with a lower TIL content, especially within the tumour microenvironment, with three lipid signals being shown to have the greatest impact on this separation (p < 0.05). On the whole, this preliminary study represents a promising starting point and suggests that a lipidomics MALDI-MSI approach could be a promising tool for subtyping the diverse immune environments in CRC.
Highlights
There is an ever-increasing body of evidence to support the central role of the tumour microenvironment (TME) and its interactions with tumour infiltrating immune cells during the process of carcinogenesis [1]
The medulla region of the thymus was considered given that it contains single positive T lymphocytes (CD4+ or CD8+, SP), in the later stages of maturation and differentiation, which may be found in the colorectal cancer tissue
From those m/z signals that followed the morphology of the medulla region of the thymus and were detected as m/z features during the feature detection pipeline, a total of 18 could be annotated using liquid chromatography coupled with mass spectrometry (LC-MS)based lipidomic approach and these are summarised in Supplementary Materials S1
Summary
There is an ever-increasing body of evidence to support the central role of the tumour microenvironment (TME) and its interactions with tumour infiltrating immune cells during the process of carcinogenesis [1] This is relevant in colorectal cancer (CRC), where those patients who progress to the later stages of the disease and present with distant metastasis, are often associated with unfavourable immune environments [2]. Studying the tissue lipidome of colorectal cancer may provide an indication of the immune environment and provide further assistance in the stratification of these patients To address this challenge, spatial lipidomics may represent an ideal tool for typing these diverse immune environments in situ given that the spatial relationship of those dysregulated lipids within the cellular network remains intact and can account for the innate molecular heterogeneity observed in CRC [12,13,14]
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