Insights into the tumor microenvironment in colorectal cancer patients

Genetic and cellular screening is essential for understanding specific cell genotypes and phenotypes, offering crucial insights into disease treatment and prognosis.

Immunohistochemistry, in particular, coupled with tissue cytometry and genetic sequencing advancements, enables in-depth analysis of the tumor microenvironment, revealing the underlying mechanisms of immunotherapy in oncology and facilitating the discovery of critical predictive biomarkers to foster more beneficial therapy and better survival rates for patients.

Metastatic colorectal cancer 

Colorectal cancer (CRC) continues to rank among the top three most common cancer types globally, affecting both men and women.1 It stands as the fifth leading cause of cancer-related death among women and the fourth among men worldwide.

Despite advancements in therapy, it is projected that the global burden of CRC will increase by 60% by 2030.2

Nearly half of CRC patients eventually develop metastases, and while clinical outcomes are improving, those with metastatic (m)CRC face a median overall survival of up to 30 months.3


Traditionally, mCRC treatment primarily involved chemotherapy with biological agents. However, there is growing evidence of the clinical benefits of immunotherapy for mCRC patients.

Immune checkpoint inhibitors (ICIs) have proven effective for various solid tumors, and recent years have seen their introduction in the treatment of mCRC patients.4

High microsatellite instability (MSI-H) and mismatch repair protein deletion (dMMR) have become vital biomarkers for stratifying patients with advanced mCRC in treatment groups.

ICIs targeting the anti-PD-1/PD-L1 pathway demonstrate significant clinical efficacy in MSI-H/dMMR patients. Unfortunately, only 5% of advanced mCRC patients exhibit MSI-H/dMMR, with the majority having microsatellite stability (MSS) and proficient mismatch repair proteins (pMMR).5

Patients with MSS/pMMR typically do not respond positively to single ICIs, and various immune combination therapy treatments have shown little benefit to patients exhibiting MSS/pMMR.

In current trials, the overall objective remission rate for patients with liver metastases stands at only 1.9%. Moreover, there are no established biomarkers for MSS-type CRC.5

The need for screening and biomarkers 

Tumors in patients with MSS-type are termed 'immune cold tumors' because they typically have low levels of lymphocyte infiltration and a low tumor mutational load, which are the main characteristics of the immune microenvironment.

To enhance the effectiveness of current immunotherapies, a combination of therapies and screening methods is employed to modify and monitor the immune microenvironment.

These treatments aim to change 'immune cold tumor' environments into 'immune hot tumors' and aid in the identification of biomarkers.5

The relationship between Tumor Mutational Burden (TMB) status and the benefits of immunotherapy in patients has been observed, although there is ongoing debate regarding the clinical significance of TMB.

Tumor-infiltrating lymphocytes (TILs) also play a significant role in predicting treatment outcomes in mCRC. However, there is a pressing need for more precise biomarkers to guide the screening of patients with MSS mCRC.

Exploring the tumor microenvironment is essential to determine which MSS-type CRC patients can derive clinical benefits from immunotherapy.5

Case study: A 50-year-old patient with mCRC/liver metastasis recovers with immunotherapy 

A 50-year-old patient diagnosed with MSS-type CRC and PD-L1-negative recurrent hepatopulmonary metastases achieved complete remission and long-lasting benefits from immunotherapy following prior unsuccessful systematic treatments.

The case study evaluated the tumor microenvironment's characteristics during the treatment to gain insights into the mechanisms behind the immunotherapy's positive effects. This allowed researchers to pinpoint phenotypes indicative of a favorable response and identify potential prognostic biomarkers.

Genetic and multiple immunohistochemical tests unveiled that mutations in DNA damage repair pathway genes and Tumor-Infiltrating Lymphocytes (TILs) likely contributed to the observed clinical benefits.

To determine cellular phenotypes associated with successful clinical outcomes, researchers employed the TissueFAXS SL platform, along with the StrataQuest image analysis solution.

TissueFAXS SL captured whole-slide images of stained tissue sections, while StrataQuest analyzed these images to quantify specific cellular phenotypes based on various immune cell markers.

This analysis revealed an enriched presence of immune cells in the tumor microenvironment, including CD8+ T cells, CD68+ macrophages, and CD163+ macrophages.

TILs are important constituents of the tumor microenvironment and can impact tumor growth, metastasis, and immunotherapy effectiveness.

In other studies, some TILs, particularly PD-1 expressing CD8+ T cells, were associated with improved survival rates in CRC.

Tumor-associated macrophages also exhibited high abundance in the tumor microenvironment and were linked to better therapeutic outcomes. This supports the notion that TILs serve as crucial indicators of immunotherapy effectiveness in MSS mCRC patients.

Mutations in DNA damage repair genes in advanced mCRC could potentially serve as essential biomarkers for screening the clinical benefits of Immune Checkpoint Inhibitors (ICIs) in MSS mCRC patients. This may expand the pool of MSS mCRC patients who can benefit from immunotherapy.


This case study highlights the substantial clinical benefits of immunotherapy, surpassing traditional chemotherapies, for advanced MSS mCRC patients.

The study underscores the need for identifying new, effective predictive biomarkers to guide the screening for immunotherapy benefits in this patient group.

With the aid of TissueFAXS and StrataQuest, researchers can unveil cellular phenotypes, immune mechanisms, and biomarkers within the tumor microenvironment, ultimately enabling the development of more effective immunotherapies.

References and further reading

  1. Ferlay, J., Colombet, M., Soerjomataram, I., Mathers, C., Parkin, D.M., Piñeros, M., Znaor, A. and Bray, F. 2019. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. International journal of cancer. 144(8), pp.1941-1953. 
  2. Arnold, M., Sierra, M.S., Laversanne, M., Soerjomataram, I., Jemal, A. and Bray, F., 2017. Global patterns and trends in colorectal cancer incidence and mortality. Gut. 66(4), pp.683-691. 
  3. Oliveira, A.F., Bretes, L. and Furtado, I., 2019. Review of PD-1/PD-L1 inhibitors in metastatic dMMR/MSI-H colorectal cancer. Frontiers in oncology. 9, p.396. 
  4. Huyghe, N., Baldin, P. and Van den Eynde, M. 2020. Immunotherapy with immune checkpoint inhibitors in colorectal cancer: what is the future beyond deficient mismatch-repair tumours? Gastroenterology report. 8(1), pp.11-24.
  5. Song, Y., Long, J., Su, X., Chen, Z., He, Y., Shao, W., Wang, B. and Chen, C. 2023. Case report: genetic and immune microenvironmental characteristics of a rectal cancer patient with MSS/PD-L1-negative recurrent hepatopulmonary metastasis who achieved complete remission after treatment with PD-1 inhibitor. Frontiers in Immunology. 14, p.1197543. 

About TissueGnostics

TissueGnostics (TG) is an Austrian company focusing on integrated solutions for high content and/or high throughput scanning and analysis of biomedical, veterinary, natural sciences, and technical microscopy samples.

TG has been founded by scientists from the Vienna University Hospital (AKH) in 2003. It is now a globally active company with subsidiaries in the EU, the USA, and China, and customers in 30 countries.

TissueGnostics portfolio

TG scanning systems are currently based on versatile automated microscopy systems with or without image analysis capabilities. We strive to provide cutting-edge technology solutions, such as multispectral imaging and context-based image analysis as well as established features like Z-Stacking and Extended Focus. This is combined with a strong emphasis on automation, ease of use of all solutions, and the production of publication-ready data.

The TG systems offer integrated workflows, i.e. scan and analysis, for digital slides or images of tissue sections, Tissue Microarrays (TMA), cell culture monolayers, smears, and other samples on slides and oversized slides, in Microtiter plates, Petri dishes and specialized sample containers. TG also provides dedicated workflows for FISH, CISH, and other dot structures.

TG analysis software apart from being integrated into full systems is fully standalone capable and supports a wide variety of scanner image formats as well as digital images taken with any microscope.

TG also provides routine hematology scanning and analysis systems for peripheral blood, bone marrow, and body fluids.

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Last updated: Nov 8, 2023 at 9:16 AM


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