Harnessing naturally occurring mutations for T-cell therapy:a potential new avenue to enhance treatment efficacy

In a recent study published in Nature,Garcia et al.use a sophisticated approach to identify fitness-enhancing mutations for T cells that was inspired by cancer evolution.1 The identified CARD11-PIK3R3 gene fusion enhanced tumor rejection and persistence of engineered T cells in multiple tumor models and might have the potential to improve efficacy of adoptive T-cell therapies in cancer patients.

Opening a window to skin biomarkers for diabetes stage with optoacoustic mesoscopy

Being the largest and most accessible organ of the human body,the skin could offer a window to diabetes-related complications on the microvasculature.However,skin microvasculature is typically assessed by histological analysis,which is not suited for applications to large populations or longitudinal studies.We introduce ultra-wideband rasterscan optoacoustic mesoscopy(RSOM)for precise,non-invasive assessment of diabetes-related changes in the dermal microvasculature and skin micro-anatomy,resolved with unprecedented sensitivity and detail without the need for contrast agents.Providing unique imaging contrast,we explored a possible role for RSOM as an investigational tool in diabetes healthcare and offer the first comprehensive study investigating the relationship between different diabetes complications and microvascular features in vivo.We applied RSOM to scan the pretibial area of 95 participants with diabetes mellitus and 48 age-matched volunteers without diabetes,grouped according to disease complications,and extracted six label-free optoacoustic biomarkers of human skin,including dermal microvasculature density and epidermal parameters,based on a novel image-processing pipeline.We then correlated these biomarkers to disease severity and found statistically significant effects on microvasculature parameters as a function of diabetes complications.We discuss how label-free RSOM biomarkers can lead to a quantitative assessment of the systemic effects of diabetes and its complications,complementing the qualitative assessment allowed by current clinical metrics,possibly leading to a precise scoring system that captures the gradual evolution of the disease.

Optoacoustic microscopy at multiple discrete frequencies

Optoacoustic(photoacoustic)sensing employs illumination of transient energy and is typically implemented in the time domain using nanosecond photon pulses.However,the generation of high-energy short photon pulses requires complex laser technology that imposes a low pulse repetition frequency(PRF)and limits the number of wavelengths that are concurrently available for spectral imaging.To avoid the limitations of working in the time domain,we have developed frequency-domain optoacoustic microscopy(FDOM),in which light intensity is modulated at multiple discrete frequencies.We integrated FDOM into a hybrid system with multiphoton microscopy,and we examine the relationship between image formation and modulation frequency,showcase high-fidelity images with increasing numbers of modulation frequencies from phantoms and in vivo,and identify a redundancy in optoacoustic measurements performed at multiple frequencies.We demonstrate that due to high repetition rates,FDOM achieves signal-to-noise ratios similar to those obtained by time-domain methods,using commonly available laser diodes.Moreover,we experimentally confirm various advantages of the frequency-domain implementation at discrete modulation frequencies,including concurrent illumination at two wavelengths that are carried out at different modulation frequencies as well as flow measurements in microfluidic chips and in vivo based on the optoacoustic Doppler effect.Furthermore,we discuss how FDOM redefines possibilities for optoacoustic imaging by capitalizing on the advantages of working in the frequency domain.

Lactate-avid regulatory T cells:metabolic plasticity controls immunosuppression in tumour microenvironment

The excellent article by Watson et al.1 points the way ahead to the important role of lactic acid/lactate-anion and glucose on the immunosuppressive activity of lactate-and glucose-affine metabolically distinct subsets of regulatory T(Treg)cells within the tumour microenvironment(TME)(Fig.1).

Spatial heterogeneity of oxygenation and haemodynamics in breast cancer resolved in vivo by conical multispectral optoacoustic mesoscopy

The characteristics of tumour development and metastasis relate not only to genomic heterogeneity but also to spatial heterogeneity,associated with variations in the intratumoural arrangement of cell populations,vascular morphology and oxygen and nutrient supply.While optical(photonic)microscopy is commonly employed to visualize the tumour microenvironment,it assesses only a few hundred cubic microns of tissue.Therefore,it is not suitable for investigating biological processes at the level of the entire tumour,which can be at least four orders of magnitude larger.In this study,we aimed to extend optical visualization and resolve spatial heterogeneity throughout the entire tumour volume.We developed an optoacoustic(photoacoustic)mesoscope adapted to solid tumour imaging and,in a pilot study,offer the first insights into cancer optical contrast heterogeneity in vivo at an unprecedented resolution of<50μm throughout the entire tumour mass.Using spectral methods,we resolve unknown patterns of oxygenation,vasculature and perfusion in three types of breast cancer and showcase different levels of structural and functional organization.To our knowledge,these results are the most detailed insights of optical signatures reported throughout entire tumours in vivo,and they position optoacoustic mesoscopy as a unique investigational tool linking microscopic and macroscopic observations.

Cytotoxic FCER1G^(+) innate-like T cells:new potential for tumour immunotherapy

In a recent study published in Nature,Chou and colleagues define a new evolutionarily conserved class of tumour-elicited immune response mediated by a distinct population of T cell receptor(TCR)-positive FCER1G-expressing innate-like T cells with high cytotoxic potential(αβILTCKs).1 Targeted immunotherapies and most prominently immune checkpoint blockade(ICB)therapies,brought clinical benefits to tumour patients that were inconceivable 15 years ago.2 These ICBs target inhibitory receptors such as PD-1 on tumour infiltrating CD8+cytotoxic T lymphocytes(CTLs)that can recognise mutated cancer cell antigens and thereby enable tumour cell killing.Yet,a significant cohort of cancer patients are non-responsive to ICB treatment and therefore,there is a strong need to discover additional anti-cancer immunomechanisms.Recent work in Nature by Chou and colleagues identifies a population ofαβILTCKs that exhibit reactivity to unmutated tumour antigens.