Systemic inflammation and pro-inflammatory cytokine profile predict response to checkpoint inhibitor treatment in NSCLC: a prospective study

Kauffmann-Guerrero, Diego; Kahnert, Kathrin; Kiefl, Rosemarie; Sellmer, Laura; Walter, Julia; Behr, Jürgen; Tufman, Amanda

doi:10.1038/s41598-021-90397-y

Cited by 52 publications

(43 citation statements)

References 28 publications

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“…Given that T-cell exhaustion is the self-protective mechanism for dysregulation of immune reaction, patients with impaired lung function might be vulnerable to ICI therapy as blockade of PD-1/PD-L1 pathway, causing airway injury, lung function decline, or pneumonitis. Additionally, analysis of circulating inflammatory markers related to ICI treatment such as neutrophil to lymphocyte ratio, LDH or CRP, which are widely used in previous studies, could provide more detailed inflammatory profiles for evaluation in the future investigation ( 38 , 39 ).…”

Section: Discussionmentioning

confidence: 99%

Reduced FEV1 as Prognostic Factors in Patients With Advanced NSCLC Receiving Immune Checkpoint Inhibitors

Shen

Chiang

et al. 2022

Front. Med.

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BackgroundThe aim of study is to investigate the influence of pulmonary function on the prognosis in patients with advanced non-small cell lung cancer (NSCLC) receiving immune checkpoint inhibitors (ICI).Patients and MethodsData were collected retrospectively from 151 patients with stage IV NSCLC who received ICI and completed spirometry before ICI therapy in Taipei Veterans General Hospital between January 2016 and December 2020. The co-primary end points were overall survival (OS) and progression-free survival (PFS) between groups divided by 80% predicted FEV1 since ICI therapy started; the secondary outcomes were objective response rate.ResultsAmong 151 patients enrolled to this study, 67.5% of patients were men, 75.5% were adenocarcinoma, 24.5% had known targetable driver mutation, 33.8% received first-line ICI, and 62.8% received ICI monotherapy. The objective response rate was 24.5% and disease control rate was 54.3%. In multivariable analysis, patient with reduced FEV1 had inferior PFS (FEV1 < 80% vs. FEV1 ≥ 80%, adjusted HR = 1.80, P = 0.006) and OS (FEV1 < 80% vs. FEV1 ≥ 80%, adjusted HR = 2.50, P < 0.001). Median PFS and OS in the preserved FEV1 group (≥80% predicted FEV1) compared to the reduced FEV1 group (<80% predicted FEV1) were 5.4 vs. 2.9 months (HR = 1.76, P = 0.003) and 34.9 vs. 11.1 months (HR = 2.44, P < 0.001), respectively. The other independent prognostic factors of OS include stage IVA disease (adjusted HR = 0.57, P = 0.037), initial liver metastasis (adjusted HR = 2.00, P = 0.049), ICI monotherapy (adjusted HR = 1.73, P = 0.042) and ICI related pneumonitis (adjusted HR = 3 .44, P = 0.025).ConclusionsReduced FEV1 is strongly associated with inferior clinical outcomes in patients with advanced NSCLC treated with ICI.

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Section: Discussionmentioning

confidence: 99%

Reduced FEV1 as Prognostic Factors in Patients With Advanced NSCLC Receiving Immune Checkpoint Inhibitors

Shen

Chiang

et al. 2022

Front. Med.

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“…On the other hand, systemic inflammation can limit tumor-specific immunity and responses to the immune-checkpoint inhibitors (ICIs). In a recent study, systemic inflammation demonstrated by increased cytokine profiles was associated with poor survival and response to the ICIs in patients with lung cancer [ 56 ]. Therefore, blood viscosity can also be a biomarker for HCC patients treated with ICIs, and future large and prospective study is needed.…”

Section: Discussionmentioning

confidence: 99%

Whole blood viscosity is associated with extrahepatic metastases and survival in patients with hepatocellular carcinoma

et al. 2021

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Whole blood viscosity (WBV) is increased in cancer patients and associated with the advanced stage with systemic metastases. However, relevance of WBV in hepatocellular carcinoma (HCC) remains unclear. This pilot study included a discovery cohort of 148 treatment-naïve HCC patients with preserved liver function, and a validation cohort of 33 treatment-experienced HCC patients with nivolumab. Systolic and diastolic WBV was measured using an automated scanning capillary tube viscometer at diagnosis or before the nivolumab treatment. Extrahepatic metastases were observed in 15 treatment-naïve patients (11.3%) at diagnosis. Portal vein tumor thrombosis (PVTT), tumor size, number of tumors, and systolic/diastolic WBV were factors associated with extrahepatic metastases. Systolic WBV and diastolic WBV were significantly increased in patients with metastases compared with patients without metastases. Multivariate logistic regression showed that high diastolic WBV > 16 cP was an independent factor associated with metastases. Notably, patients who developed extrahepatic metastases during the observation period among patients without metastases at diagnosis had higher diastolic WBV initially. Patients with high diastolic WBV had poor survival, and multivariate Cox regression analyses showed high diastolic WBV was an independent risk factor for poor survival with the Child-Pugh B7 and PVTT. High diastolic WBV also predicted poor survival in patients with low alpha-fetoprotein (AFP) and proteins induced by vitamin K antagonist-II (PIVKA-II) levels. In 33 nivolumab-treated patients, high diastolic WBV before the treatment was also tended to be associated with overall and progression-free survival. Our study is the first in which high WBV is associated with the distant metastases and survival in patients with HCC, but future prospective, large cohort studies are necessary to validate the results.

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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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Systemic inflammation and pro-inflammatory cytokine profile predict response to checkpoint inhibitor treatment in NSCLC: a prospective study

Cited by 52 publications

References 28 publications

Reduced FEV1 as Prognostic Factors in Patients With Advanced NSCLC Receiving Immune Checkpoint Inhibitors

Reduced FEV1 as Prognostic Factors in Patients With Advanced NSCLC Receiving Immune Checkpoint Inhibitors

Whole blood viscosity is associated with extrahepatic metastases and survival in patients with hepatocellular carcinoma

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

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