Immune-Modulating Effects of Conventional Therapies in Colorectal Cancer

Kalanxhi, Erta; Meltzer, Sebastian; Ree, Anne Hansen

doi:10.3390/cancers12082193

Cited by 6 publications

(4 citation statements)

References 151 publications

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“…The pro‐immunogenic role lies in its ability to promote T cell priming by inducing tumor‐associated antigens, upregulating major histocompatibility complex class‐I (MHC‐I) expression and generating an in situ vaccine [ 12 , 13 , 14 ]. In contrast, immune suppressive cells and molecules such as regulatory T cells (Tregs), myeloid‐derived suppressor cells (MDSCs), tumor‐associated macrophages (TAMs), and transforming growth factor β (TGF‐β) are stimulated by irradiation (IR) [ 15 , 16 , 17 , 18 ]. In addition, accumulating evidence demonstrates that IR‐induced cytoplasmic DNA could activate the cyclic GMP‐AMP synthase (cGAS)‐stimulator of interferon genes (STING) pathway, promoting interferon signaling and dendritic cell (DC) activation, which links DNA damage to innate immune activation and the adaptive antitumor response [ 19 , 20 ].…”

Section: Introductionmentioning

confidence: 99%

Combining radiation and the ATR inhibitor berzosertib activates STING signaling and enhances immunotherapy via inhibiting SHP1 function in colorectal cancer

Liu

Wang

Wan

et al. 2023

Cancer Communications

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Background Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 (PD‐1) and programmed death‐ligand 1 (PD‐L1) have shown a moderate response in colorectal cancer (CRC) with deficient mismatch repair (dMMR) functions and poor response in patients with proficient MMR (pMMR). pMMR tumors are generally immunogenically “cold”, emphasizing combination strategies to turn the “cold” tumor “hot” to enhance the efficacy of ICIs. ATR inhibitors (ATRi) have been proven to cooperate with radiation to promote antitumor immunity, but it is unclear whether ATRi could facilitate the efficacy of IR and ICI combinations in CRCs. This study aimed to investigate the efficacy of combining ATRi, irradiation (IR), and anti‐PD‐L1 antibodies in CRC mouse models with different microsatellite statuses. Methods The efficacy of combining ATRi, IR, and anti‐PD‐L1 antibodies was evaluated in CRC tumors. The tumor microenvironment and transcriptome signatures were investigated under different treatment regimens. The mechanisms were explored via cell viability assay, flow cytometry, immunofluorescence, immunoblotting, co‐immunoprecipitation, and real‐time quantitative PCR in multiple murine and human CRC cell lines. Results Combining ATRi berzosertib and IR enhanced CD8 + T cell infiltration and enhanced the efficacy of anti‐PD‐L1 therapy in mouse CRC models with different microsatellite statuses. The mechanistic study demonstrated that IR + ATRi could activate both the canonical cGAS‐STING‐pTBK1/pIRF3 axis by increasing cytosolic double‐stranded DNA levels and the non‐canonical STING signaling by attenuating SHP1‐mediated inhibition of the TRAF6‐STING‐p65 axis, via promoting SUMOylation of SHP1 at lysine 127. By boosting the STING signaling, IR + ATRi induced type I interferon‐related gene expression and strong innate immune activation and reinvigorated the cold tumor microenvironment, thus facilitating immunotherapy. Conclusions The combination of ATRi and IR could facilitate anti‐PD‐L1 therapy by promoting STING signaling in CRC models with different microsatellite statuses. The new combination strategy raised by our study is worth investigating in the management of CRC.

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Section: Introductionmentioning

confidence: 99%

Combining radiation and the ATR inhibitor berzosertib activates STING signaling and enhances immunotherapy via inhibiting SHP1 function in colorectal cancer

Liu

Wang

Wan

et al. 2023

Cancer Communications

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“… 68 The high TMB in these tumors has been correlated to their infiltration with neoantigen-specific T cells 69 and their response to chemotherapy 70 or immune checkpoint immunotherapy 71 , 72 : both therapies with immune-stimulating capacity. 73 , 74 Although pMMR-MSS tumors are generally considered TMB low, it has been shown that stratification of patients according to TMB predicts their overall survival following chemotherapy plus cetuximab (anti-epidermal growth factor receptor mAb) or bevacizumab (anti-vascular endothelial growth factor mAb). 68 For these tumors, the TMB can be considered a proxy for the presence of neoantigens and T cell abundance in the tumor.…”

Section: Neoantigens In Crc Immunotherapymentioning

confidence: 99%

Colorectal Cancer Immunotherapy: State of the Art and Future Directions

Cornista,

Giolito,

Baker

et al. 2023

Gastro Hep Advances

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“…According to one study, increased circulating fms-related tyrosine kinase 3 ligand (FLT3LG) caused by neoadjuvant cytotoxic treatment in rectal cancer patients activated the anti-tumor immune response. Functionally active adaptive immune cells may eliminate microscopic tumor cells, lowering the risk of tumor metastasis [ 136 ]. The combination of IL-12 gene therapy and chemotherapy has shown the ability to transform the metastatic microenvironment into a more immunogenic phenotype by reducing Treg, MDSC, and M2 macrophages [ 132 ].…”

Section: Challenges and Perspectivesmentioning

confidence: 99%

Intracellular and extracellular factors of colorectal cancer liver metastasis: a pivotal perplex to be fully elucidated

et al. 2022

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Metastasis is the leading cause of death in colorectal cancer (CRC) patients, and the liver is the most common site of metastasis. Tumor cell metastasis can be thought of as an invasion-metastasis cascade and metastatic organotropism is thought to be a process that relies on the intrinsic properties of tumor cells and their interactions with molecules and cells in the microenvironment. Many studies have provided new insights into the molecular mechanism and contributing factors involved in CRC liver metastasis for a better understanding of the organ-specific metastasis process. The purpose of this review is to summarize the theories that explain CRC liver metastasis at multiple molecular dimensions (including genetic and non-genetic factors), as well as the main factors that cause CRC liver metastasis. Many findings suggest that metastasis may occur earlier than expected and with specific organ-anchoring property. The emergence of potential metastatic clones, the timing of dissemination, and the distinct routes of metastasis have been explained by genomic studies. The main force of CRC liver metastasis is also thought to be epigenetic alterations and dynamic phenotypic traits. Furthermore, we review key extrinsic factors that influence CRC cell metastasis and liver tropisms, such as pre-niches, tumor stromal cells, adhesion molecules, and immune/inflammatory responses in the tumor microenvironment. In addition, biomarkers associated with early diagnosis, prognosis, and recurrence of liver metastasis from CRC are summarized to enlighten potential clinical practice, including some markers that can be used as therapeutic targets to provide new perspectives for the treatment strategies of CRC liver metastasis.

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Immune-Modulating Effects of Conventional Therapies in Colorectal Cancer

Cited by 6 publications

References 151 publications

Combining radiation and the ATR inhibitor berzosertib activates STING signaling and enhances immunotherapy via inhibiting SHP1 function in colorectal cancer

Combining radiation and the ATR inhibitor berzosertib activates STING signaling and enhances immunotherapy via inhibiting SHP1 function in colorectal cancer

Colorectal Cancer Immunotherapy: State of the Art and Future Directions

Intracellular and extracellular factors of colorectal cancer liver metastasis: a pivotal perplex to be fully elucidated

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