The release of negative regulators of immune activation (immune checkpoints) that limit antitumor responses has resulted in unprecedented rates of long-lasting tumor responses in patients with a variety of cancers. This can be achieved by antibodies blocking the cytotoxic T lymphocyte–associated protein 4 (CTLA-4) or the programmed cell death 1 (PD-1) pathway, either alone or in combination. The main premise for inducing an immune response is the preexistence of antitumor T cells that were limited by specific immune checkpoints. Most patients who have tumor responses maintain long-lasting disease control, yet one-third of patients relapse. Mechanisms of acquired resistance are currently poorly understood, but evidence points to alterations that converge on the antigen presentation and interferon-γ signaling pathways. New-generation combinatorial therapies may overcome resistance mechanisms to immune checkpoint therapy.

Cancer immunotherapy using checkpoint blockade

https://escholarship.org/content/qt5st231s3/qt5st231s3.pdf?t=omsseb

Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy.

To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase. Single-cell analyses suggested distinct tumor microenvironmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single-cell genomics offers insights with implications for both targeted and immune therapies.

/pdf/dissecting-the-multicellular-ecosystem-of-metastatic-1ejqc8j55d.pdf

Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq

https://thelancet.com/pdfs/journals/lancet/PIIS0140-6736(16)00561-4.pdf

Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial

Therapeutic antibodies that block the programmed death-1 (PD-1)-programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor β (TGFβ) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8+ T cells from the tumour parenchyma that were instead found in the fibroblast- and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-administration of TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFβ shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration.

/pdf/tgfb-attenuates-tumour-response-to-pd-l1-blockade-by-3tw7i2ranh.pdf

TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells.

The present invention relates to methods for predicting the probability of survival of a human melanoma cancer patient based on levels of human GDF-15, and to apparatuses and kits which can be used in these methods.

Gdf-15 as a diagnostic marker for melanoma

305 © 2016 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2016/1403 7 You R, Liu J, Li S et al. Alkali-soluble polysaccharide, isolated from Lentinus edodes, induces apoptosis and G2/M cell cycle arrest in H22 cells through microtubule depolymerization. Phytother Res 2014; 28(12): 1837–45. 8 Ren M, Ye L, Hao X et al. Polysaccharides from Tricholoma matsutake and Lentinus edodes enhance 5-fluorouracilmediated H22 cell growth inhibition. J Tradit Chin Med 2014; 34: 309–16. 9 Xu S, Xu X, Zhang L. Branching structure and chain conformation of water-soluble glucan extracted from Auricularia auricula-judae. J Agric Food Chem 2012; 60: 3498–506. 10 Reza MA, Hossain MA, Lee S et al. Dichlormethane extract of the jelly ear mushroom Auricularia auricula-judae (higher Basidiomycetes) inhibits tumor cell growth in vitro. Int J Med Mushrooms 2014; 16: 37–47. 11 Lee DH, Kim HW. Innate immunity induced by fungal betaglucans via dectin-1 signaling pathway. Int J Med Mushrooms 2014; 16: 1–16. 12 Wasser S. Medicinal mushroom science: Current perspectives, advances, evidences, and challenges. Biomed J 2014; 37(6): 345–56. 13 Lindequist U, Kim HW, Tiralongo E et al. Medicinal Mushrooms. Evid Based Complement Alternat Med 2014; 2014: 806180. 14 Scheiba N, Andrulis M, Helmbold P. Treatment of shiitake dermatitis by balneo PUVA therapy. J Am Acad Dermatol 2011; 65(2): 453–5.

Vemurafenib‐induziertes Granuloma anulare

Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment

Cutaneous metastases are particularly frequent in melanoma of the skin, and they may occur as locoregional satellite or intransit metastases or likewise as distant cutaneous metastases. In satellite and intransit metastases, achievement of complete tumor remission may result in permanent cure. Therefore, the complete tumor remission of multiple cutaneous metastases is an important therapeutic goal in a subgroup of melanoma patients.

Cutaneous Metastases of Melanoma: New Treatment Options

Primare Ziele der Nachsorge des malignen Melanoms der Haut sind die fruhzeitige Diagnose von Zweitmelanomen und Tumorrezidiven. Die Fruherkennung der Rezidive ist fur die Patienten prognoserelevant. Durch ein strukturiertes stadienadaptiertes Nachsorgeschema werden mehr als 80% der Rezidive hauptsachlich in Nachsorgeuntersuchungen erkannt. Durch die korperliche Untersuchung werden die meisten Rezidive detektiert und durch die Lymphknotensonographie wird eine Fruherkennung lokoregionarer Rezidive ermoglicht, bevor diese tastbar werden. Daruber hinaus sollten bildgebende Verfahren stadien- und risikoadaptiert eingesetzt werden, bei Melanomen im Primartumorstadium sind diese verzichtbar. Somit kann bei diesen Melanomen (besonders bei Tumordicken ≤1,0 mm) der Umfang der Untersuchungen im Vergleich zu bisherigen Empfehlungen deutlich reduziert werden. Dadurch konnen die Kosten fur die Nachsorgeuntersuchungen erheblich verringert werden, ohne das Risiko fur die Patienten deutlich zu erhohen. Im Stadium III wird eine Intensivierung der Nachsorgeuntersuchungen durch bildgebende Verfahren zur Verbesserung der Fruherkennung von Rezidiven empfohlen.

Benjamin Weide

Papers

Gdf-15 as a diagnostic marker for melanoma

Vemurafenib‐induziertes Granuloma anulare

Tumor-derived GDF-15 blocks LFA-1 dependent T cell recruitment and suppresses responses to anti-PD-1 treatment

Cutaneous Metastases of Melanoma: New Treatment Options

Nachsorge des Melanoms – neue Aspekte