The Tumor Microenvironment of Colorectal Cancer Metastases: Opportunities in Cancer Immunotherapy

Kamal, Yasmin; Schmit, Stephanie L.; Frost, H. Robert; Amos, Christopher I.

doi:10.2217/imt-2020-0026

Cited by 32 publications

(24 citation statements)

References 145 publications

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“…Mutations, including RAS, BRAF, PIK3CA, APC, TP53 mutations, and loss of PTEN expression, are usually present in metastatic CRC, and some of these genes have been suggested as promising predictive markers, and some act as predictive markers (2,3). Tumor metastasis, relapse, and drug resistance lead to poor prognosis in CRC, despite advances in CRC treatments, such as radiotherapy, surgery, and chemotherapy (4,5). Considering the high morbidity and modest effectiveness of CRC treatment, identifying reliable biomarkers of prognosis and therapeutic targets for patients with CRC is of paramount importance.…”

Section: Introductionmentioning

confidence: 99%

Significance of Kynurenine 3-Monooxygenase Expression in Colorectal Cancer

et al. 2021

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Colorectal cancer (CRC) is a leading cause of cancer-related deaths. Because of the lack of reliable prognostic and predictive biomarkers for CRC, most patients are often diagnosed at a late stage. The tryptophan–kynurenine pathway plays a crucial role in promoting cancer progression. Kynurenine is considered an oncometabolite in colon cancer, and its downstream metabolites are also associated with CRC. Kynurenine 3-monooxygenase (KMO), a pivotal enzyme that catalyzes kynurenine metabolism, is essential for several cellular processes. In the current study, we explored the role of KMO in CRC. Immunohistochemical results showed that KMO was upregulated in CRC tissues relative to paired healthy tissue and polyps. Moreover, CRC patients with higher KMO expression were associated with higher metastasis and poorer survival rates. Knockdown of KMO decreased the expression of cancer stem cell markers, as well as the sphere-forming, migration, and invasion abilities of CRC cells. Additionally, blockade of the enzymatic activity of KMO using an inhibitor suppressed sphere formation and cell motility in CRC cells. These findings suggest the clinical relevance of KMO in CRC tumorigenesis and aggressiveness.

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Section: Introductionmentioning

confidence: 99%

Significance of Kynurenine 3-Monooxygenase Expression in Colorectal Cancer

et al. 2021

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“…66 Intriguingly, the combination of oxaliplatin and cyclophosphamide with ICIs has been successfully tested. 67 Currently, the combination of ICIs with 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX) is under investigation.…”

Section: Chemotherapy and Immunotherapymentioning

confidence: 99%

“…Upon recognition of damage-associated molecular patterns or pathogenassociated molecular patterns an innate immune response is initiated. 67 In vivo studies are currently assessing the treatment efficacy of TLR agonists in combination with anti-PD-1 antibodies in colon cancers.…”

Section: Combination Of Immunotherapeutic Agents (Tlr Agonists Tfg-β mentioning

confidence: 99%

“…74 Neoadjuvant anti-EGFR antibody treatment revealed an increased PD-1 expression and CD8+ T-cell infiltration in metastases. 67 Current studies are investigating the combination of either anti-PD-1 or anti-CTLA-4 with anti-EGFR (panitumumab and cetuximab) in mCRCs.…”

Section: Combination Of Immunotherapeutic Agents (Tlr Agonists Tfg-β mentioning

confidence: 99%

“…67 Since CRCs express various tumor specific antigens such as CEA, Mucin 1 and Wilms Tumor 1, they represent an ideal option for DC therapy. 67 Despite the safety of DC-based immunotherapy, the tumor response rate upon this therapy approach is disappointing and hardly exceeds 15%. 80…”

Section: Lymphocyte-activation Gene 3 (Lag-3) and Immunotherapymentioning

confidence: 99%

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Efficacy and side effects of immune checkpoint inhibitors in the treatment of colorectal cancer

Manz

Losa

Fritsch

et al. 2021

Therap Adv Gastroenterol

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Colorectal cancers (CRCs) remain one of the most common and challenging neoplasia in the Western world. The response rate of immunotherapeutic treatment approaches in a subset of advanced CRCs is remarkable and has sustainably changed treatment regimens. Unfortunately, currently available immunotherapeutics only displayed significant antitumoral activity – in terms of progression free survival (PFS) and objective response rate (ORR) – in microsatellite instability-high (MSI-H)/DNA mismatch repair deficient (dMMR) CRCs. Subsequently, these remarkable results had led to the US Food and Drug Administration’s approval of both immune checkpoint inhibitors (ICIs) pembrolizumab and nivolumab in the treatment of advanced MSI-H/dMMR CRCs. However, in microsatellite stable (MSS)/DNA mismatch repair proficient (pMMR) CRCs, ICIs have clearly failed to meet their expectations and are therefore not considered effective. As the vast majority of CRCs display a molecular MSS/pMMR profile, current treatment approaches endeavor to improve tumor immunogenicity that consecutively leads to increased proinflammatory cytokine levels as well as tumor infiltrating T-cells, which in turn may be targeted by various immunotherapeutic agents. Therefore, ongoing studies are investigating novel synergistic therapy modalities and approaches to overcome a “cold” to “hot” tumor conversion in MSS/pMMR CRCs. In this review, we summarize the efficacy and possible immune-related adverse events as well as novel therapeutic approaches of ICIs in the treatment of MSI-H/dMMR and MSS/pMMR CRCs.

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cDC2 plasticity and acquisition of a DC3‐like phenotype mediated by IL‐6 and PGE2 in a patient‐derived colorectal cancer organoids model

Subtil,

van der Hoorn,

Cuenca‐Escalona

et al. 2024

Eur J Immunol

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Metastatic colorectal cancer (CRC) is highly resistant to therapy and prone to recur. The tumor‐induced local and systemic immunosuppression allows cancer cells to evade immunosurveillance, facilitating their proliferation and dissemination. Dendritic cells (DCs) are required for the detection, processing, and presentation of tumor antigens, and subsequently for the activation of antigen‐specific T cells to orchestrate an effective antitumor response. Notably, successful tumors have evolved mechanisms to disrupt and impair DC functions, underlining the key role of tumor‐induced DC dysfunction in promoting tumor growth, metastasis initiation, and treatment resistance. Conventional DC type 2 (cDC2) are highly prevalent in tumors and have been shown to present high phenotypic and functional plasticity in response to tumor‐released environmental cues. This plasticity reverberates on both the development of antitumor responses and on the efficacy of immunotherapies in cancer patients. Uncovering the processes, mechanisms, and mediators by which CRC shapes and disrupts cDC2 functions is crucial to restoring their full antitumor potential.In this study, we use our recently developed 3D DC‐tumor co‐culture system to investigate how patient‐derived primary and metastatic CRC organoids modulate cDC2 phenotype and function. We first demonstrate that our collagen‐based system displays extensive interaction between cDC2 and tumor organoids. Interestingly, we show that tumor‐corrupted cDC2 shift toward a CD14+ population with defective expression of maturation markers, an intermediate phenotype positioned between cDC2 and monocytes, and impaired T‐cell activating abilities. This phenotype aligns with the newly defined DC3 (CD14+ CD1c+ CD163+) subset. Remarkably, a comparable population was found to be present in tumor lesions and enriched in the peripheral blood of metastatic CRC patients. Moreover, using EP2 and EP4 receptor antagonists and an anti‐IL‐6 neutralizing antibody, we determined that the observed phenotype shift is partially mediated by PGE2 and IL‐6. Importantly, our system holds promise as a platform for testing therapies aimed at preventing or mitigating tumor‐induced DC dysfunction. Overall, our study offers novel and relevant insights into cDC2 (dys)function in CRC that hold relevance for the design of therapeutic approaches.

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The Tumor Microenvironment of Colorectal Cancer Metastases: Opportunities in Cancer Immunotherapy

Cited by 32 publications

References 145 publications

Significance of Kynurenine 3-Monooxygenase Expression in Colorectal Cancer

Significance of Kynurenine 3-Monooxygenase Expression in Colorectal Cancer

Efficacy and side effects of immune checkpoint inhibitors in the treatment of colorectal cancer

cDC2 plasticity and acquisition of a DC3‐like phenotype mediated by IL‐6 and PGE2 in a patient‐derived colorectal cancer organoids model

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