Unlocking CRC Treatment: Targeting the Fibroblast and Macrophage Partnership

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Image credit: https://openai.com/index/dall-e/  

Colorectal cancer (CRC) is a very common type of cancer, and treatment options beyond surgery can be quite limited. While immunotherapy, which helps your own immune system fight cancer, has shown great success in some cancers like melanoma and lung cancer, it's currently only effective for a small number of metastatic CRC cases. This means it's really important to understand more about the environment within and around the tumour – known as the tumour microenvironment (TME) – to find new ways to improve treatments.

This study looked closely at the cells making up the TME in CRC, analysing over 54,000 cells from both tumour tissue and nearby normal tissue. They used advanced techniques like single-cell RNA sequencing, which lets researchers see the genetic activity in individual cells, and spatial transcriptomics, which shows where different cells are located within the tissue.

One of the main findings was the identification of two specific cell types that are particularly enriched in CRC tumours compared to normal tissue: a type of stromal cell called FAP+ fibroblasts and a type of immune cell called SPP1+ macrophages. Stromal cells are essentially the structural support cells in tissues, while macrophages are a type of white blood cell involved in the immune response.

The sources show that a high number of these FAP+ fibroblasts and SPP1+ macrophages in the TME is strongly linked to worse outcomes for CRC patients, including shorter periods without the cancer progressing (progression-free survival, PFS) and shorter overall survival (OS).

Crucially, the study found that the presence of these two cell types is highly correlated. This means that if there are a lot of FAP+ fibroblasts, you're likely to find a lot of SPP1+ macrophages nearby, and vice versa. This close relationship was confirmed visually using techniques like immunofluorescence, which involves staining cells to make them visible under a microscope, and spatial transcriptomics, which shows their co-localisation within the tumour tissue.

So, where do these problematic cells come from? The research suggests that tumour-specific FAP+ fibroblasts might develop from other fibroblast subtypes like FGFR2+ fibroblasts or ICAM1+ telocytes, possibly influenced by a transcription factor called TWIST1, which itself might be regulated by low oxygen levels (hypoxia) common in tumours. SPP1+ macrophages, meanwhile, seem to originate from another macrophage subtype called THBS1+ macrophages.
The study delved into how these two cell types might interact, focusing on the signals they send and receive. They found that FAP+ fibroblasts could potentially communicate with SPP1+ macrophages through various molecules, including those involved in the TGF-β family. Interestingly, they identified a molecule called chemerin, encoded by the gene RARRES2, which is expressed at high levels in FAP+ fibroblasts. Chemerin has been shown to affect macrophage behaviour, and the receptor for chemerin (encoded by CMKLR1) is found on both THBS1+ and SPP1+ macrophages. This suggests that FAP+ fibroblasts might help drive the differentiation of THBS1+ macrophages into the tumour-promoting SPP1+ subtype via chemerin. Higher levels of chemerin were also detected in the blood plasma of CRC patients compared to healthy individuals, hinting at its potential as a marker for CRC.

The sources also propose that SPP1+ macrophages can influence FAP+ fibroblasts. By releasing signalling molecules encoded by genes like TGFB1, IL1B, and IL1A, SPP1+ macrophages appear to encourage FAP+ fibroblasts to produce components of the extracellular matrix (ECM), the material that surrounds cells in tissues.

This leads to a critical consequence: the formation of a desmoplastic structure. Desmoplasia is essentially an excessive growth of dense connective tissue within the tumour, rich in ECM components. This dense structure, often regulated by stromal cells like fibroblasts, can act as a physical barrier, preventing immune cells, particularly crucial T cells (like CD8+ T cells) that fight cancer, from getting into the tumour core. The study found that tumours with high numbers of both FAP+ fibroblasts and SPP1+ macrophages indeed showed lower infiltration of lymphocytes (a type of immune cell that includes T and B cells).

This resulting "immune-excluded" microenvironment has significant implications for immunotherapy. Since many immunotherapies, like those targeting PD-1 or PD-L1, rely on T cells reaching and attacking the tumour, their exclusion from the tumour core renders these treatments less effective. The study tested this by looking at a group of bladder cancer patients treated with anti-PD-L1 therapy. They found that patients with high levels of either FAP or SPP1 expression had shorter survival times and were less likely to respond well to the treatment compared to patients with low levels of both.

In summary, this research highlights a problematic partnership in the CRC tumour microenvironment between FAP+ fibroblasts and SPP1+ macrophages. They appear to collaborate, potentially driven by factors like chemerin and TGF-β, to create a dense, immune-excluded desmoplastic structure that shields the tumour from immune attack. This helps explain why some CRC patients don't benefit from current immunotherapies.

Therefore, disrupting this interaction between FAP+ fibroblasts and SPP1+ macrophages, or targeting the signals involved in their communication and the resulting desmoplasia, represents a promising potential strategy to improve immunotherapy outcomes for CRC patients. Future research is needed to fully understand the biological mechanisms involved.

Single-cell and spatial analysis reveal interaction of FAP+ fibroblasts and SPP1+ macrophages in colorectal cancer. Nature Communications. (2025). https://doi.org/10.1038/s41467-022-29366-6

Journal information: https://www.nature.com/ncomms/
Location: Oxford, UK

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