Peripheral natural killer cells and myeloid-derived suppressor cells correlate with anti-PD-1 responses in non-small cell lung cancer

Youn, Je In; Park, Su Myeong; Kim, Gamin; Lee, Hee Jae; Son, Jimin; Hong, Min Hee; Ghaderpour, Aziz; Baik, Bumseo; Islam, Jahirul; Choi, Ji Woong; Lee, Eun Young; Kim, Hang Rae; Seo, Sang Uk; Paik, Soonmyung; Yoon, Hong In; Jung, Inkyung; Chun, Xin; Jin, Hyun Tak; Cho, Byoung Chul; Seong, Seung Yong; Ha, Sang Jun

doi:10.1038/s41598-020-65666-x

Cited by 48 publications

(52 citation statements)

References 24 publications

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“…Just recently, it was shown for patients with NSCLC that increased amounts of peripheral NK cells correlate with responses to anti-PD-1 treatment. 45 The role for NKT cells in this scenario has not been investigated before, but it is becoming more and more evident that NKT cells are important in antitumor immunity as they, for example, reinvigorate exhausted immune cells in the tumor microenvironment. 46 Exhausted immune cells fail to contribute to antitumor immunity.…”

Section: Discussionmentioning

confidence: 99%

Prospective development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with recurrent/metastatic cancer to immune checkpoint inhibitors

Zhou

Donaubauer²,

Frey³

et al. 2021

J Immunother Cancer

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BackgroundThe predictive power of novel biological markers for treatment response to immune checkpoint inhibitors (ICI) is still not satisfactory for the majority of patients with cancer. One should identify valid predictive markers in the peripheral blood, as this is easily available before and during treatment. The current interim analysis of patients of the ST-ICI cohort therefore focuses on the development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with metastatic cancer to ICI targeting the programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) axis.MethodsA total of 104 patients were prospectively enrolled. 54 immune cell subsets were prospectively analyzed in patients’ peripheral blood by multicolor flow cytometry before treatment with ICI (pre-ICI; n=89), and after the first application of ICI (n=65). Pre-ICI, patients were randomly allocated to a training (n=56) and a validation cohort (n=33). Univariate Cox proportional hazards regression analysis and least absolute shrinkage and selection operator Cox model were used to create a predictive immune signature, which was also checked after the first ICI, to consider the dynamics of changes in the immune status.ResultsWhole blood samples were provided by 89 patients pre-ICI and by 65 patients after the first ICI. We identified a LIPS which is based on five immune cell subtypes: CD14high monocytes, CD8+/PD-1+ T cells, plasmacytoid dendritic cells, neutrophils, and CD3+/CD56+/CD16+ natural killer (NK)T cells. The signature achieved a high accuracy (C-index 0.74 vs 0.71) for predicting overall survival (OS) benefit in both the training and the validation cohort. In both cohorts, the low-risk group had significantly longer OS than the high-risk group (HR 0.26, 95% CI 0.12 to 0.56, p=0.00025; HR 0.30, 95% CI 0.10 to 0.91, p=0.024, respectively). Regarding the whole cohort, LIPS also predicted progression-free survival (PFS). The identified LIPS was not affected by clinicopathological features with the exception of brain metastases. NKT cells and neutrophils of the LIPS can be used as dynamic predictive biomarkers for OS and PFS after first administration of the ICI.ConclusionOur study identified a predictive LIPS for survival of patients with cancer treated with PD-1/PD-L1 ICI, which is based on immune cell subsets in the peripheral whole blood.Trial registration numberNCT03453892.

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Section: Discussionmentioning

confidence: 99%

Prospective development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with recurrent/metastatic cancer to immune checkpoint inhibitors

Zhou

Donaubauer²,

Frey³

et al. 2021

J Immunother Cancer

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“…Such increase in NK cell infiltration resulted in reduced primary tumor growth and metastasis. In addition, an increased ratio of NK cells to LOX-1 + PMN-MDSC predicted positive therapy response of patients with non-small cell lung carcinoma, indicating an important role of NK cell inhibition by PMN-MDSC in tumor progression [ 50 ]. Although CXCR2 was reported to be expressed also on the vascular endothelium, contributing to tumor angiogenesis [ 34 ], we failed to observe any changes in the frequency of CD31 + tumor infiltrating endothelial cells upon CXCR2 inhibition.…”

Section: Discussionmentioning

confidence: 99%

Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression

Groth

Arpinati

Shaul

et al. 2021

Cancers

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Background: Despite recent improvement in the treatment of malignant melanoma by immune-checkpoint inhibitors, the disease can progress due to an immunosuppressive tumor microenvironment (TME) mainly represented by myeloid-derived suppressor cells (MDSC). However, the relative contribution of the polymorphonuclear (PMN) and monocytic (M) MDSC subsets to melanoma progression is not clear. Here, we compared both subsets regarding their immunosuppressive capacity and recruitment mechanisms. Furthermore, we inhibited PMN-MDSC migration in vivo to determine its effect on tumor progression. Methods: Using the RET transgenic melanoma mouse model, we investigated the immunosuppressive function of MDSC subsets and chemokine receptor expression on these cells. The effect of CXCR2 inhibition on PMN-MDSC migration and tumor progression was studied in RET transgenic mice and in C57BL/6 mice after surgical resection of primary melanomas. Results: Immunosuppressive capacity of intratumoral M- and PMN-MDSC was comparable in melanoma bearing mice. Anti-CXCR2 therapy prolonged survival of these mice and decreased the occurrence of distant metastasis. Furthermore, this therapy reduced the infiltration of melanoma lesions and pre-metastatic sites with PMN-MDSC that was associated with the accumulation of natural killer (NK) cells. Conclusions: We provide evidence for the tumor−promoting properties of PMN-MDSC as well as for the anti-tumor effects upon their targeting in melanoma bearing mice.

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“…We identified increased numbers of NKT cells in patients of the ST-ICI trial to be favorable for PFS and OS. Just recently, it was shown for patients with NSCLC that increased amounts of peripheral NK cells correlate with responses to anti-PD-1 treatment [42]. The role for NKT cells in this scenario has not been investigated before, but it is becoming more and more evident that NKT cells are important in anti-tumor immunity as they e.g.…”

Section: Discussionmentioning

confidence: 99%

Development of a Flow Cytometry-Based Whole-Blood Prognostic Immune Signature in Metastatic Cancer Patients treated with immune checkpoint inhibitors

Zhou

Donaubauer

Frey

et al. 2020

Preprint

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Recent biomarker research focuses on early immunological changes to predict treatment response to immune checkpoint inhibitors (ICI). Within this prospective ST-ICI trial, pre-planned biomarker analysis was performed and we developed a flow cytometry-based whole-blood prognostic immune signature (FCBPS) to predict overall survival (OS) benefit of cancer patients treated with ICI. For this, fifty-four immune cell subsets were analyzed in the patients peripheral blood before the second administration of the ICI. Patients were randomly allocated to a training and validation cohort. Univariate Cox proportional hazards regression analysis and LASSO Cox model were used to develop a predictive and prognostic signature. 104 patients were prospectively enrolled. 89 patients provided blood samples. The identified FCBPS signature bases on five immune cell subtypes: neutrophils, plasmacytoid dendritic cells (pDCs), natural killer (NK)T cells (CD56+/CD16+), monocytes (CD14high) and CD8+ T cells (PD-1+). This signature achieved a high accuracy (C-index 0.74 vs 0.71) for predicting OS benefit in the training and validation cohort. Both in the training and validation cohort, the low-risk group had significantly longer OS than the high-risk group (HR 0.26, 95% CI: 0.12-0.56, p=0.00025; HR 0.30, 95% CI: 0.10 -0.91, p=0.024, respectively). In the whole cohort, FCBPS is a predictor of OS (HROS=0.28, 95% CI: 0.15-0.52) and progression-free survival (HRPFS=0.22, 95% CI: 0.12-0.39) that remained independent in multivariate analyses and subgroup analyses after adjusting for clinical and pathological factors. The identified flow cytometry-based whole-blood prognostic signature (FCBPS) is a powerful predictor for metastatic cancer patients who benefit from ICI treatment.

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Peripheral natural killer cells and myeloid-derived suppressor cells correlate with anti-PD-1 responses in non-small cell lung cancer

Cited by 48 publications

References 24 publications

Prospective development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with recurrent/metastatic cancer to immune checkpoint inhibitors

Prospective development and validation of a liquid immune profile-based signature (LIPS) to predict response of patients with recurrent/metastatic cancer to immune checkpoint inhibitors

Blocking Migration of Polymorphonuclear Myeloid-Derived Suppressor Cells Inhibits Mouse Melanoma Progression

Development of a Flow Cytometry-Based Whole-Blood Prognostic Immune Signature in Metastatic Cancer Patients treated with immune checkpoint inhibitors

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