Chemotherapy ± Cetuximab Modulates Peripheral Immune Responses in Metastatic Colorectal Cancer

Xynos, Ioannis; Karadima, Maria L.; Voutsas, Ioannis F.; Amptoulach, Sousana; Skopelitis, Elias; Kosmas, Christos; Gritzapis, Angelos D.; Tsavaris, Nikolas

doi:10.1159/000343282

Cited by 13 publications

(9 citation statements)

References 73 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Studies in APC min/+ mice models have revealed a novel EGFR-independent oncogenic signal of EGF in the tumor microenvironment [61]. So, strategies that target immune effectors including CD15/FUT4, LY6G6D/F, CD137, CD73, or NK-activating targets may enhance the efficacy of anti-EGFR therapies (Figure 2) [41,42,63,64,65,66,67,68,69,70]. Furthermore, mCRC patients treated with cetuximab plus chemo-therapy show altered cytokine production by the peripheral blood cells after treatment (specifically, an increase in IL-2, IFN-γ, IL-12, and IL-18, and a decrease in IL-4 and IL-10) which correlated with the response to therapy.…”

Section: Contribution Of Tumor Microenvironment To Acquired Resistmentioning

confidence: 99%

Immune Resistance and EGFR Antagonists in Colorectal Cancer

Giordano

Remo²,

Porrás

et al. 2019

Cancers

View full text Add to dashboard Cite

: Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy in patients with RAS wild type metastatic colorectal cancer (mCRC) has revolutionized the treatment of CRC, but with less results than initially envisaged. In recent years, the discovery of multiple pathways leading to the escape from anti-EGFR therapy has revealed an enormous complexity and heterogeneity of human CRC due to the intrinsic genomic instability and immune/cancer cell interaction. Therefore, understanding the mechanistic basis of acquired resistance to targeted therapies represents a major challenge to improve the clinical outcomes of patients with CRC. The latest findings strongly suggest that complex molecular alterations coupled with changes of the immune tumor microenvironment may substantially contribute to the clinical efficacy of EGFR antagonist. In this review, we discuss the most recent findings that contribute to both primary and acquired anti-EGFR therapy resistance. In addition, we analyze how strategies aiming to enhance the favorable effects in the tumor microenvironment may contribute to overcome resistance to EGFR therapies.

show abstract

Section: Contribution Of Tumor Microenvironment To Acquired Resistmentioning

confidence: 99%

Immune Resistance and EGFR Antagonists in Colorectal Cancer

Giordano

Remo²,

Porrás

et al. 2019

Cancers

View full text Add to dashboard Cite

show abstract

“…IL‐18 production was increased in peripheral blood mononuclear cells obtained from colorectal cancer patients who were treated with irinotecan‐based regimens (Xynos et al . ). However, none of the studies outlined here assessed the contributions of IL‐18 to the pathogenesis of intestinal disease.…”

Section: Introductionmentioning

confidence: 97%

“…In addition, Leach et al (2008) found increased local and systemic IL-18 and IL-18bp production in patients with inflammatory bowel disease, suggesting that this cytokine may contribute to local inflammatory changes. IL-18 production was increased in peripheral blood mononuclear cells obtained from colorectal cancer patients who were treated with irinotecan-based regimens (Xynos et al 2013).…”

Section: Introductionmentioning

confidence: 99%

Targeted inhibition of IL‐18 attenuates irinotecan‐induced intestinal mucositis in mice

Lima-Júnior

Freitas

Wong

et al. 2014

British J Pharmacology

View full text Add to dashboard Cite

Background and Purpose Intestinal mucositis is a common side‐effect of irinotecan‐based cancer chemotherapy regimens. This mucositis is associated with cytokine activation and NO synthesis. Production of IL‐18 is up‐regulated in patients suffering from inflammatory bowel disease. Therefore, we have investigated the role of IL‐18 in the pathogenesis of irinotecan‐induced intestinal mucositis. Experimental Approach Wild type (WT), IL‐18 or caspase‐1 knockout mice were treated with either saline or irinotecan (60 mg·kg−1 per 4 days, i.p.) or the IL‐18 binding protein (IL‐18bp, 10 mg·kg−1) before irinotecan. On day 5, diarrhoea was monitored and proximal intestinal strips were obtained for histopathology, in vitro gut contractility, myeloperoxidase (MPO) and inducible NOS (iNOS) activity, and detection of IL‐18 expression. Key Results Irinotecan induced severe diarrhoea accompanied by intestinal injury (villi shortening and increased crypt depth). Additionally, irinotecan treatment increased MPO and iNOS activity, iNOS immunostaining and IL‐18 expression in WT mice compared with saline treatment. The IL‐18 production was associated with macrophages. In vitro, intestinal smooth muscle strips were hyperresponsive to ACh after irinotecan treatment. Increases in MPO and iNOS activity, intestinal contractility and diarrhoea were prevented in caspase‐1 knockout and IL‐18 knockout mice, and in IL‐18bp‐treated WT mice. Furthermore, the Survival of irinotecan‐treated mice was increased and iNOS immunoexpression and IL‐18 production prevented in IL‐18 knockout mice. Conclusions and Implications Targeting IL‐18 function may be a promising therapeutic approach to decreasing the severity of intestinal mucositis during irinotecan treatment regimens.

show abstract

“…Of note, several lines of evidence suggest that CPT-11-triggered diarrhoea is associated with the production of the pro-inflammatory cytokines IL-1β and IL-18 [20], suggesting an immunogenic response. Previous studies have also demonstrated an anticancer effect of CPT-11-associated anti-tumour immunity [21]. Consequently, we consider CPT-11-induced diarrhoea as an ideal model to dissect the mechanism of the interplay between immunogenic response-associated anti-tumour efficacy and the adverse effects of chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation

et al. 2017

View full text Add to dashboard Cite

Chemotherapies are known often to induce severe gastrointestinal tract toxicity but the underlying mechanism remains unclear. This study considers the widely applied cytotoxic agent irinotecan (CPT-11) as a representative agent and demonstrates that treatment induces massive release of double-strand DNA from the intestine that accounts for the dose-limiting intestinal toxicity of the compound. Specifically, "self-DNA" released through exosome secretion enters the cytosol of innate immune cells and activates the AIM2 (absent in melanoma 2) inflammasome. This leads to mature IL-1β and IL-18 secretion and induces intestinal mucositis and late-onset diarrhoea. Interestingly, abrogation of AIM2 signalling, either in AIM2-deficient mice or by a pharmacological inhibitor such as thalidomide, significantly reduces the incidence of drug-induced diarrhoea without affecting the anticancer efficacy of CPT-11. These findings provide mechanistic insights into how chemotherapy triggers innate immune responses causing intestinal toxicity, and reveal new chemotherapy regimens that maintain anti-tumour effects but circumvent the associated adverse inflammatory response.

show abstract

Chemotherapy ± Cetuximab Modulates Peripheral Immune Responses in Metastatic Colorectal Cancer

Cited by 13 publications

References 73 publications

Immune Resistance and EGFR Antagonists in Colorectal Cancer

Immune Resistance and EGFR Antagonists in Colorectal Cancer

Targeted inhibition of IL‐18 attenuates irinotecan‐induced intestinal mucositis in mice

Chemotherapy-induced intestinal inflammatory responses are mediated by exosome secretion of double-strand DNA via AIM2 inflammasome activation

Contact Info

Product

Resources

About