The Role of Cytokines in Predicting the Response and Adverse Events Related to Immune Checkpoint Inhibitors

Wang, Min; Zhai, Xuechao; Li, Ji; Guan, Jingyuan; Su, Xu; Li, Yuying; Zhu, Hui

doi:10.3389/fimmu.2021.670391

Cited by 67 publications

(74 citation statements)

References 143 publications

(168 reference statements)

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“…Cytokines that are secreted by immune cells such as macrophages, activated T-cells, B-cells and NK cells take a lead in irAEs pathophysiology. Increased levels of IFN-γ and IFN-γ pathway genes are positive biomarkers of tumor response on ICI treatment and irAEs and IL-8, IL-6, and TGF-β are negative biomarkers ( 22 ). Experimental study evaluated cardiomyocyte cell line showed an increase of IL-1β, IL-8, IL-6, and TGF-β after Nivolumab and Ipilimumab affection ( 23 ).…”

Section: Discussionmentioning

confidence: 99%

Myocardial PD-L1 Expression in Patients With Ischemic and Non-ischemic Heart Failure

Кушнарева

Kushnarev

Artemyeva

et al. 2022

Front. Cardiovasc. Med.

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Objective: Immune checkpoints inhibitors are promising and wide-spread agents in anti-cancer therapy. However, despite their efficacy, these agents could cause cardiotoxicity, a rare but life-threatening event. In addition, there are still no well-described predictive factors for the development of immune-related adverse events and information on high risk groups. According to known experimental studies we hypothesized that cardiovascular diseases may increase myocardial PD-L1 expression, which could be an extra target for Checkpoint inhibitors and a potential basis for complications development.Methods: We studied patterns of myocardial PD-L1 expression in non-cancer-related cardiovascular diseases, particularly ischemic heart disease (n = 12) and dilated cardiomyopathy (n = 7), compared to patients without known cardiovascular diseases (n = 10) using mouse monoclonal anti-PD-L1 antibody (clone 22C3, 1:50, Dako). Correlation between immunohistochemical data and echocardiographic parameters was assessed. Statistical analyses were performed using R Statistical Software—R studio version 1.3.1093.Results: In the myocardium of cardiac patients, we found membranous, cytoplasmic, and endothelial expression of PD-L1 compared to control group. In samples from patients with a history of myocardial infarction, PD-L1 membrane and endothelial expression was more prominent and frequent, and cytoplasmic and intercalated discs staining was more localized. In contrast, samples from patients with dilated cardiomyopathy displayed very faint endothelial staining, negative membrane staining, and more diffuse PD-L1 expression in the cytoplasm and intercalated discs. In samples from the non-cardiac patients, no convincing PD-L1 expression was observed. Moreover, we discovered a significant negative correlation between PD-L1 expression level and left ventricular ejection fraction and a positive correlation between PD-L1 expression level and left ventricular end-diastolic volume.Conclusions: The present findings lay the groundwork for future experimental and clinical studies of the role of the PD-1/PD-L1 pathway in cardiovascular diseases. Further studies are required to find patients at potentially high risk of cardiovascular adverse events associated with immune checkpoint inhibitors therapy.

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Section: Discussionmentioning

confidence: 99%

Myocardial PD-L1 Expression in Patients With Ischemic and Non-ischemic Heart Failure

Кушнарева

Kushnarev

Artemyeva

et al. 2022

Front. Cardiovasc. Med.

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“…proposed [64][65][66] . Moreover, IL-1α blocking agents have already been tested in clinical trials on patients with various tumors and with different grading, showing variable efficiency 41,42,44,64 .…”

Section: Discussionmentioning

confidence: 99%

“…In addition, considering the variability of cytokines levels and responses to cytokines-based therapies in patients 61 , IL-1α blockade could be envisaged as an alternative to IL-6 inhibition for boosting STAT3i 62 in those patients with low levels of IL-6 and low sensitivity to IL-6 depletion 63 . The specific cytokines expression profiling in patients, in fact, might be a useful tool to predict the patient response to the treatment and to design the best therapeutic strategy, according to the concept of personalized medicine, as previously proposed [64][65][66] . Moreover, IL-1α blocking agents have already been tested in clinical trials on patients with various tumors and with different grading, showing variable efficiency 41,42,44,64 .…”

Section: Discussionmentioning

confidence: 99%

IL-1α secreted by subcapsular sinus macrophages promotes melanoma metastasis in the sentinel lymph node by upregulating STAT3 signaling in the tumor

Virgilio

Bordini

Sartori

et al. 2021

Preprint

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During melanoma metastasization, tumor cells originated in the skin migrate via lymphatic vessels to the sentinel lymph node (sLN) in a process that facilitates their spread across the body. Here, we characterized the innate inflammatory responses to melanoma metastasis in the sLN. For this purpose, we confirmed the migration of fluorescent metastatic melanoma cells to the sLN and we characterized the inflammatory response in the metastatic microenvironment. We found that macrophages located in the subcapsular sinus (SSM), produce pro-tumoral IL-1α after recognition of tumor antigens. Moreover, we confirmed that the administration of an anti-IL-1α depleting antibody reduced metastasis. Conversely, the administration of recombinant IL-1α accelerated the lymphatic spreading of the tumor. Additionally, the elimination of the macrophages significantly reduced the progression of the metastatic spread. To understand the mechanism of action of IL-1α in the context of the lymph node microenvironment, we applied single-cell RNA sequencing to dissected metastases obtained from animals treated with an anti-IL-1α blocking antibody. Amongst the different pathways affected, we identified STAT3 as one of the main targets of IL-1α signaling in metastatic cells. Moreover, we found that the anti-IL-1α anti-tumoral effect was not mediated by lymphocytes, as IL-1R1 KO mice did not show any improvement in metastasis growth. Finally, we found a synergistic anti-metastatic effect of the combination of IL-1α blocking and the STAT3 inhibitor (STAT3i) stattic. In summary, we described a new mechanism by which SSM support melanoma metastasis, highlighting a new target for immunotherapy.

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“…Candidate cytokine biomarkers for CRC include APRIL, BAFF, IL8 and MMP2, which are inversely correlated with immune cell infiltration and expression of CD163, a marker of M2 macrophages [ 203 ]. Another investigation revealed that IL-17A increased expression of PD-L1 on CRC cells and that inhibition of IL-17A improved the efficacy of anti-PD-1 therapy in a murine MSS CRC model [ 204 , 205 ]. Further investigation and validation is needed to translate use of these biomarkers into the clinic.…”

Section: Predictive Biomarkers For Response To It In Colorectal Cancermentioning

confidence: 99%

Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers

Carlsen

Huntington

El‐Deiry

2022

Cancers

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Though early-stage colorectal cancer has a high 5 year survival rate of 65–92% depending on the specific stage, this probability drops to 13% after the cancer metastasizes. Frontline treatments for colorectal cancer such as chemotherapy and radiation often produce dose-limiting toxicities in patients and acquired resistance in cancer cells. Additional targeted treatments are needed to improve patient outcomes and quality of life. Immunotherapy involves treatment with peptides, cells, antibodies, viruses, or small molecules to engage or train the immune system to kill cancer cells. Preclinical and clinical investigations of immunotherapy for treatment of colorectal cancer including immune checkpoint blockade, adoptive cell therapy, monoclonal antibodies, oncolytic viruses, anti-cancer vaccines, and immune system modulators have been promising, but demonstrate limitations for patients with proficient mismatch repair enzymes. In this review, we discuss preclinical and clinical studies investigating immunotherapy for treatment of colorectal cancer and predictive biomarkers for response to these treatments. We also consider open questions including optimal combination treatments to maximize efficacy, minimize toxicity, and prevent acquired resistance and approaches to sensitize mismatch repair-proficient patients to immunotherapy.

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The Role of Cytokines in Predicting the Response and Adverse Events Related to Immune Checkpoint Inhibitors

Cited by 67 publications

References 143 publications

Myocardial PD-L1 Expression in Patients With Ischemic and Non-ischemic Heart Failure

Myocardial PD-L1 Expression in Patients With Ischemic and Non-ischemic Heart Failure

IL-1α secreted by subcapsular sinus macrophages promotes melanoma metastasis in the sentinel lymph node by upregulating STAT3 signaling in the tumor

Immunotherapy for Colorectal Cancer: Mechanisms and Predictive Biomarkers

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