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Heregger, R.; Huemer, F.; Steiner, M.; Gonzalez-Martinez, A.; Greil, R.; Weiss, L. Cell Types in dMMR/MSI-H Colorectal Cancer. Encyclopedia. Available online: https://encyclopedia.pub/entry/51687 (accessed on 30 July 2024).
Heregger R, Huemer F, Steiner M, Gonzalez-Martinez A, Greil R, Weiss L. Cell Types in dMMR/MSI-H Colorectal Cancer. Encyclopedia. Available at: https://encyclopedia.pub/entry/51687. Accessed July 30, 2024.
Heregger, Ronald, Florian Huemer, Markus Steiner, Alejandra Gonzalez-Martinez, Richard Greil, Lukas Weiss. "Cell Types in dMMR/MSI-H Colorectal Cancer" Encyclopedia, https://encyclopedia.pub/entry/51687 (accessed July 30, 2024).
Heregger, R., Huemer, F., Steiner, M., Gonzalez-Martinez, A., Greil, R., & Weiss, L. (2023, November 16). Cell Types in dMMR/MSI-H Colorectal Cancer. In Encyclopedia. https://encyclopedia.pub/entry/51687
Heregger, Ronald, et al. "Cell Types in dMMR/MSI-H Colorectal Cancer." Encyclopedia. Web. 16 November, 2023.
Cell Types in dMMR/MSI-H Colorectal Cancer
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This entry is adapted from the peer-reviewed paper 10.3390/cancers15205090

Mismatch-repair deficient (dMMR)/microsatellite instability high (MSI-H) cancers encompass a subset of colorectal cancers (CRCs) sensitive to immune checkpoint inhibitors (ICIs). Nevertheless, nearly 30% of patients with dMMR/MSI-H CRC show primary resistance to ICIs, and some develop resistance in the course of disease. 

colorectal cancer mismatch-repair deficiency microsatellite instability immune checkpoint inhibitors

1. Introduction

Colorectal cancer (CRC) is a significant global health concern, ranking as the third most common cancer diagnosis and the second leading cause of cancer-related deaths in 2020 [1][2][3][4]. In Europe, it accounts for one-eighth of all cancer diagnoses, making it the second most prevalent tumor type [5]. With incidences of early CRC cases rising by 1% to 4% annually in high-income countries [1], there is an urgent need for effective treatment strategies. Immune checkpoint inhibitors (ICIs)—alone or in combination with chemotherapy—have demonstrated considerable clinical efficacy in a wide range of cancer types and have therefore emerged as a cornerstone of standard treatments in many cancers. The effectiveness of ICIs in CRC is limited to patients with mismatch-repair-deficient (dMMR)/microsatellite instability high (MSI-H) disease. This subtype accounts for about 15% of all CRC localized cases [6][7] and only 3% to 5% of metastatic colorectal cancer (mCRC) cases [8][9]. dMMR/MSI-H CRC can arise due to either sporadic or hereditary causes. One out of eight dMMR/MSI-H CRCs cases are sporadic and occur due to somatic promoter hypermethylation of the MutL homolog 1 (MLH1) gene [10]. Hereditary cases are mainly associated with Lynch syndrome and result from germline mutations in one of the MMR genes, such as MLH1, PMS1 homolog 2 (PMS2), MutS homolog 2 (MSH2), and MutS homolog 6 (MSH6) or a mutation of the EPCAM gene. When compared to their mismatch-repair-proficient(pMMR)/microsatellite stable (MSS) counterpart, dMMR/MSI-H CRCs typically exhibit specific tumor characteristics. These include poor differentiation, a high frequency of BRAF mutations, and a tendency for the primary tumor to be located in the right colon [8][11].
The advent of ICIs has revolutionized the treatment landscape for metastatic dMMR/MSI-H CRC. In the phase III clinical trial KEYNOTE-177 and the phase II trial CHECKMATE-142, disease control rates of 65% using pembrolizumab and 84% using a combination treatment of nivolumab and ipilimumab were observed [12][13]. These results underscore the significant potential of ICIs in managing dMMR/MSI-H mCRC, with the median progression-free survival (PFS) extending to 16.5 months compared to 8.2 months with standard chemotherapy and biological agents. As a result, pembrolizumab has been established as a new standard for first-line therapy in these patients [12], with nivolumab and ipilimumab being considered for second-line therapy [13].

2. Cell Types Involved in Tumor Immune Evasion in Mismatch-Repair Deficient (dMMR)/Microsatellite Instability High (MSI-H) Colorectal Cancer

The tumor environment contains various immune cells, such as CD4+ and CD8+ T cells, natural killer cells, regulatory T cells (Tregs), and myeloid-derived suppressor cells (MDSCs). These cells interact in intricate ways that can either promote or hinder tumor growth. T lymphocytes, particularly CD8+ cytotoxic T cells and CD4+ helper T cells, are crucial in distinguishing self from foreign antigens, with the help of antigen-presenting cells like dendritic cells. However, the activation of these T cells can be negatively regulated by immune checkpoint molecules such as cytotoxic T lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3), and lymphocyte activation gene 3 (LAG-3) [14]. This regulation can lead to peripheral tolerance and T-cell exhaustion, reducing the effectiveness of the immune response against the tumor.

2.1. Regulatory T Cells

Tregs play a key role in maintaining immune homeostasis by limiting the inflammation caused by effector T cells [15][16]. They achieve this through the release of inhibitory cytokines like interleukin (IL) 10 and transforming growth factor β (TGF-β), or by modulating antigen-presenting cells through the expression of CTLA-4 or LAG-3 [17][18]. However, their role in CRC is still unclear due to conflicting findings on their prognostic significance. For instance, Salama et al. found that the presence of Tregs in CRC was associated with improved survival outcomes [19][20]. On the contrary, Waniczek et al. reported that high Treg infiltration was linked to poor disease-free survival (DFS) and overall survival (OS) [21]. Although these results have been obtained primarily in tumors presumed to be pMMR/MSS, they shed a light on the diversity of Tregs, which include both activated and non-suppressive subtypes.
These subtypes consist of suppressive cluster of differentiation (CD) 45RA+ forkhead-box-protein P3 (FOXP3) high naive-like cells, suppressive CD45RA–FOXP3-high effector Treg cells, and pro-inflammatory CD45RA–FOXP3-low effector Treg cells [22]. Saito et al. found that high FOXP3 expression was linked to poorer prognosis in CRC patients, with tumor-infiltrating Tregs primarily being suppressive effector Tregs (CD45RA–FOXP3-high) [23]. Targeting these suppressive Tregs or their inhibitory cytokines might be a strategy to overcome resistance to ICIs. For instance, antibodies against IL-10 have been shown to increase the presence of tumor-infiltrating lymphocytes (TILs) and promote tumor cell death in vitro [24]. While earlier studies have noted an increase in FOXP3 positive cells in dMMR/MSI-H CRC [25][26], the specific function of these Tregs in facilitating immune evasion in MSI-H CRC tumors is yet to be fully understood.

2.2. Myeloid-Derived Suppressor Cells

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of immune cells from the myeloid lineage and can suppress anti-tumor immunity through different mechanisms [27]:
  • Enzyme Production: MDSCs produce enzymes such as nitric oxide synthase and arginase-1, which deplete L-arginine, an amino acid that is essential for the normal functioning of T cells and the T-cell receptor [28][29]. This depletion impairs the immune response against tumors.
  • Interaction with Tregs: there is evidence to suggest that MDSCs can stimulate the activation of Tregs through the release of the cytokine IL-10 [30], which leads to immunosuppression.
Even though there is a higher prevalence of intratumoral Tregs and MDSCs in pMMR/MSS CRC compared to dMMR/MSI CRC [31], dMMR/MSI tumors might be more susceptible to the effects of these immunosuppressive cells.

2.3. Tumor-Associated Macrophages

Tumor-associated macrophages (TAMs) are generally found in the microenvironment of solid tumors and can be classified into M1 (proinflammatory) and M2 (anti-inflammatory) subtypes [32]. M1 macrophages, typically activated by interferon-γ (IFN-γ) or tumor necrosis factors, possess cytotoxic effects against cancer cells [33][34]. IL-4 is one of several cytokines responsible for activating M2 macrophages, which exhibit anti-inflammatory and pro-tumor characteristics [35]. This polarization state is not permanent, allowing macrophages to switch between the M1 and M2 phenotypes [35]. The role of these macrophages in CRC is debated, with some studies linking high TAM density to improved outcomes [36][37] and others suggesting the opposite [38].
Specific studies on dMMR/MSI-H CRC tumors have shown a higher prevalence of intratumoral M1 macrophages [39] and elevated expression levels of PD-L1 on M2 macrophages at the invasive front [40] in comparison to pMMR/MSS tumors.
To date, three strategies have been explored to target TAMs as a potential cancer treatment: inhibiting TAM recruitment, reprogramming pro-tumoral M2 macrophages to the anti-tumoral M1 phenotype, or a combination of both [41][42].

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Subjects: Oncology
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Ronald Heregger
,
Florian Huemer
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Markus Steiner
,
Alejandra Gonzalez-Martinez
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Richard Greil
,
Lukas Weiss
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