Prediction of tumor-reactive T cell receptors from scRNA-seq data for personalized T cell therapy.

The identification of patient-derived, tumor-reactive T cell receptors (TCRs) as a basis for personalized transgenic T cell therapies remains a time- and cost-intensive endeavor. Current approaches to identify tumor-reactive TCRs analyze tumor mutations to predict T cell activating (neo)antigens and use these to either enrich tumor infiltrating lymphocyte (TIL) cultures or validate individual TCRs for transgenic autologous therapies. Here we combined high-throughput TCR cloning and reactivity validation to train predicTCR, a machine learning classifier that identifies individual tumor-reactive TILs in an antigen-agnostic manner based on single-TIL RNA sequencing. PredicTCR identifies tumor-reactive TCRs in TILs from diverse cancers better than previous gene set enrichment-based approaches, increasing specificity and sensitivity (geometric mean) from 0.38 to 0.74. By predicting tumor-reactive TCRs in a matter of days, TCR clonotypes can be prioritized to accelerate the manufacture of personalized T cell therapies.

[Brain tumor immunotherapy-Possibilities and challenges of personalization]. / Hirntumorimmuntherapie ­ Möglichkeiten und Herausforderungen der Personalisierung.

Brain tumors represent a special interdisciplinary challenge in the treatment of neurological disorders. Insights into the interindividual as well as the spatial and temporal intraindividual heterogeneity require entirely new personalized treatment approaches. Particularly in the field of immunotherapy there are possibilities for targeted interventions and systematic follow-up for assessment of response to treatment. Although not yet integrated into the standard treatment, early clinical trials in recent years have shown the feasibility of systematic personalized treatment approaches. The conceptual and regulatory implications of these approaches reach far beyond the field of neuro-oncology.

Emerging targets for anticancer vaccination: IDH.

The development of anticancer vaccines as a pillar of cancer immunotherapy has been hampered by the scarcity of suitable tumor-specific antigens. While response to immune checkpoint inhibitors is driven by T cells recognizing mutated antigens, the vast majority of these neoantigens are patient-specific, mandating personalized approaches. In addition, neoantigens are often subclonal present in only a fraction of tumor cells resulting in immune evasion of neoantigen-negative tumor cells. Isocitrate dehydrogenase (IDH)1 mutations, most frequently encoding for the neomorphic protein IDH1R132H, are frequent driver mutations found in the majority of diffuse World Health Organization grade 2 and 3 gliomas. In addition, IDH1R132H generates a shared clonal neoepitope that is recognized by mutation-specific T-helper cells. A recent phase 1 trial (NOA-16, NCT02454634) demonstrated safety and immunogenicity of IDH1-vac, a long IDH1R132H peptide vaccine in patients with newly diagnosed astrocytoma and provided evidence of biological efficacy based on imaging parameters. In addition, vaccine-induced IDH1R132H-reactive tumor-infiltrating T cells were identified. Here we discuss clinical and scientific implications and future developments of IDH-directed immunotherapies.

The aryl hydrocarbon receptor links integrin signaling to the TGF-ß pathway.

Glioblastoma is the most common and aggressive form of intrinsic brain tumor. Transforming growth factor (TGF)-ß represents a central mediator of the malignant phenotype of these tumors by promoting invasiveness and angiogenesis, maintaining tumor cell stemness and inducing profound immunosuppression. Integrins, which are highly expressed in glioma cells, interact with the TGF-ß pathway. Furthermore, a link has been described between activity of the transcription factor aryl hydrocarbon receptor (AhR) and TGF-ß expression. Here we demonstrate that integrin inhibition, using αv, ß3 or ß5 neutralizing antibodies, RNA interference-mediated integrin gene silencing or pharmacological inhibition by the cyclic RGD peptide EMD 121974 (cilengitide) or the non-peptidic molecule GLPG0187, inhibits AhR activity. These effects are independent of cell detachment or cell density. While AhR mRNA expression was not affected by integrin inhibition, AhR total and nuclear protein levels were reduced, suggesting that integrin inhibition-mediated regulation of AhR may occur at a post-transcriptional level. AhR-null astrocytes, AhR-null hepatocytes or glioblastoma cells with a transiently silenced AhR gene showed reduced sensitivity to integrin inhibition-mediated alterations in TGF-ß signaling, indicating that AhR mediates integrin control of the TGF-ß pathway. Accordingly, there was a significant correlation of αv integrin levels with nuclear AhR and pSmad2 levels as determined by immunohistochemistry in human glioblastoma in vivo. In summary, this study identifies a signaling network comprising integrins, AhR and TGF-ß and validates integrin inhibition as a promising strategy not only to inhibit angiogenesis, but also to block AhR- and TGF-ß-controlled features of malignancy in human glioblastoma.

Visible skin colouration predicts perception of male facial age, health and attractiveness.

Although there is evidence that perception of facial age, health and attractiveness is informed by shape characteristics as well as by visible skin condition, studies on the latter have focused almost exclusively on female skin. Recent research, however, suggests that a decrease in skin colour homogeneity leads to older, less healthy and less attractive ratings of facial skin in both women and men. Here, we elaborate on the significance of the homogeneity of visible skin colouration in men by testing the hypothesis that perception of age, health and attractiveness of (non-contextual) digitally isolated fields of cheek skin only can predict that of whole facial images. Facial digital images of 160 British men (all Caucasian) aged between 10 and 70 were blind-rated for age, health and attractiveness by a total of 147 men and 154 women (mean age = 22.95, SD = 4.26), and these ratings were related to those of corresponding images of cheek skin reported by Fink et al. (J. Eur. Acad. Dermatol. Venereol. in press). Linear regression analysis showed that age, health and attractiveness perception of men's faces could be predicted by the ratings of cheek skin only, such that older men were viewed as older, less healthy and less attractive. This result underlines once again the potent signalling role of skin in its own right, independent of shape or other factors and suggests strongly that visible skin condition, and skin colour homogeneity in particular, plays a significant role in the perception of men's faces.

Colour homogeneity and visual perception of age, health and attractiveness of male facial skin.

BACKGROUND: Visible facial skin condition in females is known to affect perception of age, health and attractiveness. Skin colour distribution in shape- and topography-standardized female faces, driven by localized melanin and haemoglobin, can account for up to twenty years of apparent age perception. Although this is corroborated by an ability to discern female age even in isolated, non-contextual skin images, a similar effect in the perception of male skin is yet to be demonstrated. OBJECTIVES: To investigate the effect of skin colour homogeneity and chromophore distribution on the visual perception of age, health and attractiveness of male facial skin. METHODS: Cropped images from the cheeks of facial images of 160 Caucasian British men aged 10-70 years were blind-rated for age, health and attractiveness by a total of 308 participants. In addition, the homogeneity of skin images and corresponding eumelanin/oxyhaemoglobin concentration maps were analysed objectively using Haralick's image segmentation algorithm. RESULTS: Isolated skin images taken from the cheeks of younger males were judged as healthier and more attractive. Perception of age, health and attractiveness was strongly related to melanin and haemoglobin distribution, whereby more even distributions led to perception of younger age and greater health and attractiveness. The evenness of melanized features was a stronger cue for age perception, whereas haemoglobin distribution was associated more strongly with health and attractiveness perception. CONCLUSIONS: Male skin colour homogeneity, driven by melanin and haemoglobin distribution, influences perception of age, health and attractiveness.