Hojjatipour, Tahereh
(2025)
T-cell and macrophage exhaustion in the colorectal cancer microenvironment and impact on survival.
MRes thesis, University of Nottingham.
Abstract
Colorectal cancer (CRC) is one of the most common cancers worldwide. In recent years, attention has turned to the role of immune cells within the tumour microenvironment (TME). Immunoscore is one development that histopathologically classifies CRC based on the differences in the immune architecture of CD3+ and CD8+ T-cells. However, the colorectal TME is complex than this and more comprehensive approaches are required to map and interpret its composition. T cells and macrophages are abundant in the CRC TME, and their composition and functionality can significantly impact patient prognosis and survival. In particular, T cell exhaustion, characterized by non-functional bystander T cells expressing immune checkpoint molecules, plays a critical role in fostering malignant TME to promote cancer growth. Macrophages are also manipulated to favor tumour growth; however, there is limited data on their expression of checkpoint molecules.
The CRC TME is well-established as one of the most diverse tumour microenvironments among solid cancers. Many studies have described the prognostic impact of macrophages and T cells, and the impact of factors such as tumour sidedness (right vs. left), mismatch repair (MMR) status (MSI vs. MSS), sample location (invasive margin, luminal side, tumour center, and adjacent normal tissue), and tumour grade/stage. With the advent of improved immune spatial platforms, we conducted a comprehensive exploration of the distribution and prognostic impact of T cells and macrophages that expressed PD1, LAG3, and TIM3 checkpoint molecules.
Multiplex immunohistochemistry was applied to a tissue microarray representing 1,000 CRC patients each described by four cores from different pathological locations. Spatial analysis identified five distinct regions within the CRC TME and using Cytomaps identified a region characterized by a high density of macrophages and T cells. We found that the density of all studied checkpoint molecules was greater on macrophages and T cells in the stromal compartment compared to those in the intraepithelial regions. Notably, PD1 was expressed significantly more in T cells than in macrophages, while macrophages predominantly expressed TIM3. Intraepithelial infiltration of T cells associated with improved survival, regardless of the exhaustion markers or other variables analyzed in this study. In contrast, CD68 did not demonstrate prognostic value on its own; however, it may indicate a favorable prognosis at the invasive margins of MSS-CRC, particularly on the right side, during both early and advanced stages. Additionally, PD1 expression on T cells correlated with better survival outcomes, whereas the expression of TIM3 on both macrophages and T cells associated with reduced survival. LAG3 was not expressed in macrophages, and its expression on T cells did not provide prognostic value.
Our findings underscore the need to consider the location and interactions of immune cells with and without checkpoint molecules within the CRC tumour microenvironment, not just their overall expression levels. Future research in this area is vital for creating effective, personalized immunotherapy treatments.
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