scholarly journals Characterization of a Myeloid Activation Signature That Correlates with Survival in Melanoma Patients

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1431
Author(s):  
Mirela Kremenovic ◽  
Nives Rombini ◽  
Alfred A. Chan ◽  
Thomas Gruber ◽  
Lukas Bäriswyl ◽  
...  
Keyword(s):  
Overall Survival ◽  
Checkpoint Inhibitors ◽  
Myeloid Cells ◽  
Poly I:C ◽  
Cellular Interactions ◽  
Therapeutic Modalities ◽  
Signature Genes ◽  
Melanoma Model ◽  
Melanoma Patients

Understanding the cellular interactions within the tumor microenvironment (TME) of melanoma paved the way for novel therapeutic modalities, such as T cell-targeted immune checkpoint inhibitors (ICI). However, only a limited fraction of patients benefits from such therapeutic modalities, highlighting the need for novel predictive and prognostic biomarkers. As myeloid cells orchestrate the tumor-specific immune response and influence the efficacy of ICI, assessing their activation state within the TME is of clinical relevance. Here, we characterized a myeloid activation (MA) signature, comprising the three genes Cxcl11, Gbp1, and Ido1, from gene expression data of human myeloid cells stimulated with poly(I:C) or cGAMP. This MA signature positively correlated to overall survival in melanoma. In addition, increased expression of the MA signature was observed in melanoma patients responding to ICI (anti-PD-1), as compared to non-responders. Furthermore, the MA signature was validated in the murine B16F10 melanoma model where it was induced and associated with decreased tumor growth upon intratumoral administration of poly(I:C) and cGAMP. Finally, we were able to visualize co-expression of the MA signature genes in myeloid cells of human melanoma tissues using RNAscope in situ hybridization. In conclusion, the MA signature indicates the activation state of myeloid cells and represents a prognostic biomarker for the overall survival in melanoma patients.

scholarly journals Checkpoint inhibitor induced hepatitis and the relation with liver metastasis and outcome in advanced melanoma patients

2021 ◽  
Author(s):  
Maaike Biewenga ◽  
Monique K. van der Kooij ◽  
Michel W. J. M. Wouters ◽  
Maureen J. B. Aarts ◽  
Franchette W. P. J. van den Berkmortel ◽  
...  
Keyword(s):  
Overall Survival ◽  
Liver Metastasis ◽  
Combination Therapy ◽  
Real World ◽  
Cytotoxic T Lymphocyte ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Negative Effect ◽  
Melanoma Patients

Abstract Background Checkpoint inhibitor-induced hepatitis is an immune-related adverse event of programmed cell death protein 1 (PD-1) inhibition, cytotoxic T-lymphocyte associated 4 (CTLA-4) inhibition or the combination of both. Aim of this study was to assess whether checkpoint inhibitor-induced hepatitis is related to liver metastasis and outcome in a real-world nationwide cohort. Methods Data from the prospective nationwide Dutch Melanoma Treatment Registry (DMTR) was used to analyze incidence, risk factors of checkpoint inhibitor-induced grade 3–4 hepatitis and outcome. Results 2561 advanced cutaneous melanoma patients received 3111 treatments with checkpoint inhibitors between May 2012 and January 2019. Severe hepatitis occurred in 30/1620 (1.8%) patients treated with PD-1 inhibitors, in 29/1105 (2.6%) patients treated with ipilimumab and in 80/386 (20.7%) patients treated with combination therapy. Patients with hepatitis had a similar prevalence of liver metastasis compared to patients without hepatitis (32% vs. 27%; p = 0.58 for PD-1 inhibitors; 42% vs. 29%; p = 0.16 for ipilimumab; 38% vs. 43%; p = 0.50 for combination therapy). There was no difference in median progression free and overall survival between patients with and without hepatitis (6.0 months vs. 5.4 months progression-free survival; p = 0.61; 17.0 vs. 16.2 months overall survival; p = 0.44). Conclusion Incidence of hepatitis in a real-world cohort is 1.8% for PD-1 inhibitor, 2.6% for ipilimumab and 20.7% for combination therapy. Checkpoint inhibitor-induced hepatitis had no relation with liver metastasis and had no negative effect on the outcome.

scholarly journals EXTH-12. RADIATION ENHANCES MELANOMA RESPONSE TO IMMUNOTHERAPY AND SYNERGIZES WITH BENZODIAZEPINES TO PROMOTE ANTI-TUMOR ACTIVITY

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi84-vi84
Author(s):  
Daniel Pomeranz Krummel ◽  
Tahseen Nasti ◽  
Benjamin Izar ◽  
Maxwell Xu ◽  
Lindsey Lowder ◽  
...  
Keyword(s):  
Gabaa Receptors ◽  
Checkpoint Inhibitors ◽  
Rna Seq ◽  
Treatment Groups ◽  
Combination Strategies ◽  
Melanoma Model ◽  
Melanoma Patients ◽  
The Impact ◽  
Anti Tumor Activity ◽  
Systemic Therapies

Abstract Melanoma brain metastases (MBM) occur in ~50% of advanced melanoma patients. It is unclear if systemic therapies synergize with radiotherapy (RT) and what the impact of RT timing has on efficacy. We find that RT followed by ICI (immune checkpoint inhibitors) (RTàICI) improves MBM patient survival compared to other combination strategies, also shown here in a murine melanoma model. RNA-seq of MBM tumors in the RTàICI group exhibit overrepresentation of genes implicated in NFKB signaling. There is also expression of GABAA receptor subunits across both treatment groups. We show that melanoma cells express functional GABAA receptors and that benzodiazepines impair tumor growth. Combination of sub-lethal RT doses with benzodiazepine results in significant ipsilateral and out of field abscopal anti-tumor activity, which is associated with enhanced tumor infiltration with poly-functional CD8 T-cells. This study provides evidence that RT enhances MBM response to ICI and synergizes with benzodiazepines to promote anti-tumor activity.

Correlated Studies of Cellular Interactions Using TEM, Freeze Etching, and SEM

1974 ◽  
Vol 32 ◽  
pp. 320-321
Author(s):  
J. P. Revel
Keyword(s):  
Developmental Stages ◽  
Three Dimensional ◽  
Cell Movement ◽  
Cellular Interactions ◽  
Serial Sections ◽  
Cell Sheets ◽  
Freeze Etching ◽  
Early Developmental

Movement of individual cells or of cell sheets and complex patterns of folding play a prominent role in the early developmental stages of the embryo. Our understanding of these processes is based on three- dimensional reconstructions laboriously prepared from serial sections, and from autoradiographic and other studies. Many concepts have also evolved from extrapolation of investigations of cell movement carried out in vitro. The scanning electron microscope now allows us to examine some of these events in situ. It is possible to prepare dissections of embryos and even of tissues of adult animals which reveal existing relationships between various structures more readily than used to be possible vithout an SEM.

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