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Background Intratumoral heterogeneity (ITH) and subclonal antigen expression blunt antitumor immunity and are associated with poor responses to immune-checkpoint blockade immunotherapy (ICB) in patients with cancer. The underlying mechanisms however thus far remained elusive, preventing the design of novel treatment approaches for patients with high ITH tumors.Methods We developed a mouse model of lung adenocarcinoma with defined expression of different neoantigens (NeoAg), enabling us to analyze how these impact antitumor T-cell immunity and to study underlying mechanisms. Data from a large cancer patient cohort was used to study whether NeoAg architecture characteristics found to define tumor immunogenicity in our mouse models are linked to ICB responses in patients with cancer.Results We demonstrate that concurrent expression and clonality define NeoAg architectures which determine the immunogenicity of individual NeoAg and drive immune evasion of tumors with heterogenous NeoAg expression. Mechanistically, we identified concerted interplays between concurrent T-cell responses induced by cross-presenting dendritic cells (cDC1) mirroring the tumor NeoAg architecture during T-cell priming in the lymph node. Depending on the characteristics and clonality of respective NeoAg, this interplay mutually benefited concurrent T-cell responses or led to competition between T-cell responses to different NeoAg. In tumors with heterogenous NeoAg expression, NeoAg architecture-induced suppression of T-cell responses against branches of the tumor drove immune evasion and caused resistance to ICB. Therapeutic RNA-based vaccination targeting immune-suppressed T-cell responses synergized with ICB to enable control of tumors with subclonal NeoAg expression. A pan-cancer clinical data analysis indicated that competition and synergy between T-cell responses define responsiveness to ICB in patients with cancer.Conclusions NeoAg architectures modulate the immunogenicity of NeoAg and tumors by dictating the interplay between concurrent T-cell responses mediated by cDC1. Impaired induction of T-cell responses supports immune evasion in tumors with heterogenous NeoAg expression but is amenable to NeoAg architecture-informed vaccination, which in combination with ICB portrays a promising treatment approach for patients with tumors exhibiting high ITH.

Prostate artery embolization (PAE) is emerging as a safe and efficacious treatment which approaches benign prostatic obstruction (BPO) from a unique perspective. This brings with it distinct advantages and solutions, which we discuss along with cost, evidence, complications and disadvantages.

ABSTRACT Objectives The objective was to develop a framework for incorporating patient engagement into administrative health database research. In an examination of variation in high-cost health service use using administrative data, patient experience was incorporated as an additional source of knowledge to inform evidence-informed policy making in a learning healthcare system framework. Method The study described variation in the rate of high-cost use by area within Nova Scotia, Canada, and isolated local factors contributing to the rate of high-cost use to inform targeted intervention development. Regression analysis was used to determine where the rate of high-cost use was driven by known contributors, such as demographics or disease patterns. Peer-leaders from provincial chronic disease management programs (Patient Navigators) were recruited as study team members. They were invited to help describe their collective experience of patient-based factors that may contribute to high-cost use, including access to care and multi-morbidity in their regions. Results The outcome of this ‘proxy’ patient engagement was measured by the extent to which the input from the Patient Navigators influenced study protocol, interpretation of results and communication of findings. The patient voice helped describe the extent of variation, contextualize the findings, and suggested additional contributory factors not revealed by the analysis of administrative health data. For example, the Patient Navigators described regional discrepancies in available services for managing chronic disease and variation in the approach to discharge planning. In this way, the patient experience was incorporated to attempt to explain rates of high-cost use in areas that could not be explained by known contributors. Further, patient experience with travel distance to receive care and alternate levels of care helped to generate questions for future research. Conclusion Patient experience is an invaluable input into health research that contributes to health system planning. This research incorporated ‘proxy’ patient experience to produce evidence to inform targeted interventions aimed at reducing the rate of high cost-users. The identified areas where focused interventions or reforms could yield material benefits for efficient delivery of health care.