How the Tumor Micromilieu Modulates the Recruitment and Activation of Colorectal Cancer-Infiltrating Lymphocytes

Atreya, Imke; Neurath, Markus F.

doi:10.3390/biomedicines10112940

Cited by 5 publications

(3 citation statements)

References 148 publications

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“…Admittedly, TME also has a hand in recruitment and activation of cytotoxic immune cells, which comprises a constellation of immunomodulatory cytokines/chemokines and suppressive immune cells, thus, determining responsiveness of CRC to immunotherapeutic agents 99 . As proof, CMS1 is characterized by high infiltration of cytotoxic T cells and Th1 cells, and upregulation of multiple immune checkpoints 100 .…”

Section: Preclinical and Clinical Evidence For Crc Subtypingmentioning

confidence: 99%

Molecular subtypes of colorectal cancer in the era of precision oncotherapy: Current inspirations and future challenges

Dang,

Zuo,

et al. 2024

Cancer Medicine

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BackgroundColorectal cancer (CRC) is among the most hackneyed malignancies. Even patients with identical clinical symptoms and the same TNM stage still exhibit radically different clinical outcomes after receiving equivalent treatment regimens, indicating extensive heterogeneity of CRC. Myriad molecular subtypes of CRC have been exploited for decades, including the most compelling consensus molecular subtype (CMS) classification that has been broadly applied for patient stratification and biomarker‐drug combination formulation. Encountering barriers to clinical translation, however, CMS classification fails to fully reflect inter‐ or intra‐tumor heterogeneity of CRC. As a consequence, addressing heterogeneity and precisely managing CRC patients with unique characteristics remain arduous tasks for clinicians.ReviewIn this review, we systematically summarize molecular subtypes of CRC and further elaborate on their clinical applications, limitations, and future orientations.ConclusionIn recent years, exploration of subtypes through cell lines, animal models, patient‐derived xenografts (PDXs), organoids, and clinical trials contributes to refining biological insights and unraveling subtype‐specific therapies in CRC. Therapeutic interventions including nanotechnology, clustered regulatory interspaced short palindromic repeat/CRISPR‐associated nuclease 9 (CRISPR/Cas9), gut microbiome, and liquid biopsy are powerful tools with the possibility to shift the immunologic landscape and outlook for CRC precise medicine.

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Section: Preclinical and Clinical Evidence For Crc Subtypingmentioning

confidence: 99%

Molecular subtypes of colorectal cancer in the era of precision oncotherapy: Current inspirations and future challenges

Dang,

Zuo,

et al. 2024

Cancer Medicine

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“…FOXP3-positive T helper cells function as regulatory T cells (Tregs) and interfere with effective cytotoxic immune responses. In colorectal cancer, Th17 cells are known as protumorigenic immune cells that lead to a worse prognosis [31,32]. Additionally, CMS4 tumors express chemokines such as CCL-2, CCL-5 and CXCL-12 that attract myeloid cells, leading to the infiltration of cancerassociated fibroblasts (CAFs), MDSCs and tumor-associated macrophages (TAMs) [25,33].…”

Section: Differences Between Cold Altered-excluded Altered-immunosupp...mentioning

confidence: 99%

T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment

Zheng

Wieder

Mauerer

et al. 2023

IJMS

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Therapeutic options for metastatic colorectal cancer (mCRC) are very limited, and the prognosis using combination therapy with a chemotherapeutic drug and a targeted agent, e.g., epidermal growth factor receptor or tyrosine kinase, remains poor. Therefore, mCRC is associated with a poor median overall survival (mOS) of only 25–30 months. Current immunotherapies with checkpoint inhibitor blockade (ICB) have led to a substantial change in the treatment of several cancers, such as melanoma and non-small cell lung cancer. In CRC, ICB has only limited effects, except in patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient (dMMR) tumors, which comprise about 15% of sporadic CRC patients and about 4% of patients with metastatic CRC. The vast majority of sporadic CRCs are microsatellite-stable (MSS) tumors with low levels of infiltrating immune cells, in which immunotherapy has no clinical benefit so far. Immunotherapy with checkpoint inhibitors requires the presence of infiltrating T cells into the tumor microenvironment (TME). This makes T cells the most important effector cells in the TME, as evidenced by the establishment of the immunoscore—a method to estimate the prognosis of CRC patients. The microenvironment of a tumor contains several types of T cells that are anti-tumorigenic, such as CD8+ T cells or pro-tumorigenic, such as regulatory T cells (Tregs) or T helper 17 (Th17) cells. However, even CD8+ T cells show marked heterogeneity, e.g., they can become exhausted, enter a state of hyporesponsiveness or become dysfunctional and express high levels of checkpoint molecules, the targets for ICB. To kill cancer cells, CD8+ T cells need the recognition of the MHC class I, which is often downregulated on colorectal cancer cells. In this case, a population of unconventional T cells with a γδ T cell receptor can overcome the limitations of the conventional CD8+ T cells with an αβT cell receptor. γδ T cells recognize antigens in an MHC-independent manner, thus acting as a bridge between innate and adaptive immunity. Here, we discuss the effects of different T cell subsets in colorectal cancer with a special emphasis on γδ T cells and the possibility of using them in CAR-T cell therapy. We explain T cell exclusion in microsatellite-stable colorectal cancer and the possibilities to overcome this exclusion to enable immunotherapy even in these “cold” tumors.

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“…Rectal carcinomas, like any human tumor, are readily recognized by peripheral lymphocytes and monocytes that infiltrate the tumor stroma. Chemokine secretion by cancer and stroma cells greatly contributes to the attraction of inflammatory cells from the bloodstream [9]. One of the first studies focusing on the appraisal of TIL-density in hematoxylin and eosin tissue sections from 98 patients with rectal cancer found a striking difference among cases, with a TIL-density ranging from less than 10 to more than 100 lymphocytes per ×40 high-power optical field [10].…”

Section: Tumor-infiltrating Lymphocytes (Tils) 21 Overall Til-densitymentioning

confidence: 99%

Immune Response and Immune Checkpoint Molecules in Patients with Rectal Cancer Undergoing Neoadjuvant Chemoradiotherapy: A Review

Koukourakis

Platoni

Tiniakos

et al. 2023

CIMB

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It is well-established that tumor antigens and molecules expressed and secreted by cancer cells trigger innate and adaptive immune responses. These two types of anti-tumor immunity lead to the infiltration of the tumor’s microenvironment by immune cells with either regulatory or cytotoxic properties. Whether this response is associated with tumor eradication after radiotherapy and chemotherapy or regrowth has been a matter of extensive research through the years, mainly focusing on tumor-infiltrating lymphocytes and monocytes and their subtypes, and the expression of immune checkpoint and other immune-related molecules by both immune and cancer cells in the tumor microenvironment. A literature search has been conducted on studies dealing with the immune response in patients with rectal cancer treated with neoadjuvant radiotherapy or chemoradiotherapy, assessing its impact on locoregional control and survival and underlying the potential role of immunotherapy in the treatment of this cancer subtype. Here, we provide an overview of the interactions between local/systemic anti-tumor immunity, cancer-related immune checkpoint, and other immunological pathways and radiotherapy, and how these affect the prognosis of rectal cancer patients. Chemoradiotherapy induces critical immunological changes in the tumor microenvironment and cancer cells that can be exploited for therapeutic interventions in rectal cancer.

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How the Tumor Micromilieu Modulates the Recruitment and Activation of Colorectal Cancer-Infiltrating Lymphocytes

Cited by 5 publications

References 148 publications

Molecular subtypes of colorectal cancer in the era of precision oncotherapy: Current inspirations and future challenges

Molecular subtypes of colorectal cancer in the era of precision oncotherapy: Current inspirations and future challenges

T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment

Immune Response and Immune Checkpoint Molecules in Patients with Rectal Cancer Undergoing Neoadjuvant Chemoradiotherapy: A Review

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