Skin-resident innate lymphoid cells converge on a pathogenic effector state.

Tissue-resident innate lymphoid cells (ILCs) help sustain barrier function and respond to local signals. ILCs are traditionally classified as ILC1, ILC2 or ILC3 on the basis of their expression of specific transcription factors and cytokines1. In the skin, disease-specific production of ILC3-associated cytokines interleukin (IL)-17 and IL-22 in response to IL-23 signalling contributes to dermal inflammation in psoriasis. However, it is not known whether this response is initiated by pre-committed ILCs or by cell-state transitions. Here we show that the induction of psoriasis in mice by IL-23 or imiquimod reconfigures a spectrum of skin ILCs, which converge on a pathogenic ILC3-like state. Tissue-resident ILCs were necessary and sufficient, in the absence of circulatory ILCs, to drive pathology. Single-cell RNA-sequencing (scRNA-seq) profiles of skin ILCs along a time course of psoriatic inflammation formed a dense transcriptional continuum-even at steady state-reflecting fluid ILC states, including a naive or quiescent-like state and an ILC2 effector state. Upon disease induction, the continuum shifted rapidly to span a mixed, ILC3-like subset also expressing cytokines characteristic of ILC2s, which we inferred as arising through multiple trajectories. We confirmed the transition potential of quiescent-like and ILC2 states using in vitro experiments, single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) and in vivo fate mapping. Our results highlight the range and flexibility of skin ILC responses, suggesting that immune activities primed in healthy tissues dynamically adapt to provocations and, left unchecked, drive pathological remodelling.

Diversity of the National Medical Student Body - Four Decades of Inequities.

A racially and ethnically diverse health care workforce remains a distant goal, the attainment of which is contingent on the inclusivity of the national medical student body. We examined the diversity of medical school applicants and enrollees over the past four decades with an eye toward assessing the progress made. Data on the gender and race or ethnic group of enrollees in all medical doctorate degree-granting U.S. medical schools from 1978 through 2019 were examined. The percentage of female enrollees doubled during this period, and women now constitute more than half the national medical student body. This upturn has been attributed largely to an increase by a factor of 12 in the enrollment of Asian women. The corresponding decrease in the percentage of male enrollees, most notably White men, was offset by an increase by a factor of approximately 5 in the enrollment of Asian men. The percentages of enrollees from Black, Hispanic, and other racial and ethnic groups that are underrepresented in medicine remain well below the percentages of these groups in the national Census.

Integration of immuno-oncology with stereotactic radiosurgery in the management of brain metastases.

AIM: Brain metastases traditionally carried a poor prognosis with treatment being a combination of surgery, whole-brain radiation therapy, and glucocorticoids; however, this treatment paradigm carried a significant amount of morbidity. In recent years, stereotactic radiosurgery (SRS), which involves the delivery of a highly conformal dose of radiation over a single session, has been shown to be an effective alternative to WBRT with excellent rates of local control and improved quality of life; however, a survival benefit has not been demonstrated. Recent developments have challenged the traditional view of the central nervous system being "immunologically privileged" which has led to a greater focus on treating these patients with systemic therapies. Immune checkpoint inhibitors (ICI) have been shown to improve survival in multiple malignancies. As a result, there has been increased utilization in combining these therapies in this setting. METHODS: We conducted a literature search of medical databases (e.g. PubMed) for articles involving the use of immune checkpoint inhibitors and stereotactic radiosurgery in managing brain metastases. RESULTS: Published evidence utilizing SRS and ICI is largely limited to single institution and retrospective in nature with the most common histology being melanoma. CONCLUSION: Combination therapy with SRS and ICI appears to improve survival in patients with brain metastases. The available data are largely retrospective; therefore, ongoing and planned prospective studies are needed to further validate these findings.

Evaluating the Role of Family Context Within a Randomized Adolescent HIV-Risk Prevention Trial.

Project STYLE is a multi-site 3-arm RCT comparing family-based, adolescent-only, and general health promotion interventions with 721 adolescents in mental health treatment. This study reports 12-month outcomes for family context and sexual risk behaviors, and explores the role of baseline family context in modifying treatment response. Using the full sample, there were sustained benefits for parent-reported sexual communication (d = 0.28), and adolescent-reported parental monitoring (d = 0.24), with minimal differences in risk behaviors. Latent profile analysis identified four family context classes: struggling (n = 177), authoritative (n = 183), authoritarian (n = 175), and permissive (n = 181). The authoritarian and permissive classes were also distinguished by disagreement between parent and adolescent report of family context. Classes differed in terms of baseline mental health burden and baseline sexual risk behavior. Classes showed different patterns of treatment effects, with the struggling class showing consistent benefit for both family context and sexual risk. In contrast, the authoritarian class showed a mixed response for family context and increased sexual risk.

A Protective Function of IL-22BP in Ischemia Reperfusion and Acetaminophen-Induced Liver Injury.

Acute liver injury can be secondary to a variety of causes, including infections, intoxication, and ischemia. All of these insults induce hepatocyte death and subsequent inflammation, which can make acute liver injury a life-threatening event. IL-22 is a dual natured cytokine which has context-dependent protective and pathogenic properties during tissue damage. Accordingly, IL-22 was shown to promote liver regeneration upon acute liver damage. However, other studies suggest pathogenic properties of IL-22 during chronic liver injury. IL-22 binding protein (IL-22BP, IL-22Ra2) is a soluble inhibitor of IL-22 that regulates IL-22 activity. However, the significance of endogenous IL-22BP in acute liver injury is unknown. We hypothesized that IL-22BP may play a role in acute liver injury. To test this hypothesis, we used Il22bp-deficient mice and murine models of acute liver damage induced by ischemia reperfusion and N-acetyl-p-aminophenol (acetaminophen) administration. We found that Il22bp-deficient mice were more susceptible to acute liver damage in both models. We used Il22 × Il22bp double-deficient mice to show that this effect is indeed due to uncontrolled IL-22 activity. We could demonstrate mechanistically increased expression of Cxcl10 by hepatocytes, and consequently increased infiltration of inflammatory CD11b+Ly6C+ monocytes into the liver in Il22bp-deficient mice upon liver damage. Accordingly, neutralization of CXCL10 reversed the increased disease susceptibility of Il22bp-deficient mice. In conclusion, our data indicate that IL-22BP plays a protective role in acute liver damage, via controlling IL-22-induced Cxcl10 expression.

Stereotactic Radiosurgery and Immune Checkpoint Inhibitors in the Management of Brain Metastases.

Brain metastases traditionally carried a poor prognosis with an overall survival of weeks to months in the absence of treatment. Radiation therapy modalities include whole brain radiation therapy (WBRT) and stereotactic radiosurgery (SRS). WBRT delivers a relatively low dose of radiation, has neurocognitive sequelae, and has not been investigated for its immunostimulatory effects. Furthermore, WBRT exposes the entire intracranial tumor immune microenvironment to radiation. SRS delivers a high dose of conformal radiation with image guidance to minimize dose to surrounding normal brain tissue, and appears to promote anti-tumor immunity. In parallel with many of these discoveries, immune checkpoint inhibitors (ICIs) have demonstrated a survival advantage in multiple malignancies commonly associated with brain metastases (e.g., melanoma). Combination SRS and ICI are theorized to be synergistic in anti-tumor immunity directed to brain metastases. The purpose of this review is to explore the synergy of SRS and ICIs, including pre-clinical data, existing clinical data, and ongoing prospective trials.

Interpersonal Autonomic Physiology: A Systematic Review of the Literature.

Interpersonal autonomic physiology is defined as the relationship between people's physiological dynamics, as indexed by continuous measures of the autonomic nervous system. Findings from this field of study indicate that physiological activity between two or more people can become associated or interdependent, often referred to as physiological synchrony. Physiological synchrony has been found in both new and established relationships across a range of contexts, and it correlates with a number of psychosocial constructs. Given these findings, interpersonal physiological interactions are theorized to be ubiquitous social processes that co-occur with observable behavior. However, this scientific literature is fragmented, making it difficult to evaluate consistency across reports. In an effort to facilitate more standardized scholarly approaches, this systematic review provides a description of existing work in the area and highlights theoretical, methodological, and statistical issues to be addressed in future interpersonal autonomic physiology research.

Surgical referral coordination from a first-level hospital: a prospective case study from rural Nepal.

BACKGROUND: Patients in isolated rural communities typically lack access to surgical care. It is not feasible for most rural first-level hospitals to provide a full suite of surgical specialty services. Comprehensive surgical care thus depends on referral systems. There is minimal literature, however, on the functioning of such systems. METHODS: We undertook a prospective case study of the referral and care coordination process for cardiac, orthopedic, plastic, gynecologic, and general surgical conditions at a district hospital in rural Nepal from 2012 to 2014. We assessed the referral process using the World Health Organization's Health Systems Framework. RESULTS: We followed the initial 292 patients referred for surgical services in the program. 152 patients (52%) received surgery and four (1%) suffered a complication (three deaths and one patient reported complication). The three most common types of surgery performed were: orthopedics (43%), general (32%), and plastics (10%). The average direct and indirect cost per patient referred, including food, transportation, lodging, medications, diagnostic examinations, treatments, and human resources was US$840, which was over 1.5 times the local district's per capita income. We identified and mapped challenges according to the World Health Organization's Health Systems Framework. Given the requirement of intensive human capital, poor quality control of surgical services, and the overall costs of the program, hospital leadership decided to terminate the referral coordination program and continue to build local surgical capacity. CONCLUSION: The results of our case study provide some context into the challenges of rural surgical referral systems. The high relative costs to the system and challenges in accountability rendered the program untenable for the implementing organization.

A Preliminary Investigation of a Tool to Measure BCBA Supervisory Behaviors.

Board certified behavior analysts (BCBAs) are in high demand. However, given the fast growth of the field, most behavior analysts who serve as supervisors have recently been certified and thus, have had limited opportunities to refine their supervisory repertoires. Although supervision best practices have been a topic of frequent discussion in behavior analytic publications, little research has been conducted to empirically assess these recommendations with BCBA supervisors. One reason for the lack of research may be due to the scarcity of a method to systematically identify and measure supervisory behaviors. The Operant Supervisory Taxonomy and Index (OSTI; Komaki, 1986Journal of Applied Psychology, 71(2), 270-279, 1998) was developed to identify and categorize supervisory behaviors of effective supervisors in organizational settings. To demonstrate the feasibility of the OSTI with BCBA supervision, this study applied the OSTI with two masters-level students completing a verified course sequence (VCS) as a part of pursing their BCBA credential. Future directions for research and application of the OSTI as a measurement framework for BCBA supervisory behavior and behavior analytic training are discussed.

Combined Regional Approach of Talimogene laherparepvec and Radiotherapy in the Treatment of Advanced Melanoma.

Talimogene laherparepvec (TVEC) is a genetically modified oncolytic herpes simplex virus (HSV-1) that is used for the intralesional treatment of advanced or metastatic melanoma. Given that TVEC produces the granulocyte-macrophage colony-stimulating factor (GM-CSF), recent reports have suggested that radiation treatment (RT) given in conjunction with TVEC may provide synergistic immune activation at the site, and possibly systemically. However, studies on combining RT with TVEC remain limited. We conducted a retrospective review of melanoma patients from a single cancer center who received TVEC and RT in the same region of the body and compared them to patients who received TVEC with RT at another site (other than the site of TVEC injection). Between January 2015 and September 2022, we identified twenty patients who were treated with TVEC and RT; fourteen patients received TVEC and RT in the same region, and six had treatments in separate regions. Regions were determined at the time of analysis and were based on anatomic sites (such as arm, leg, torso, etc.). Kaplan-Meier analysis of progression-free survival (PFS), analyses of time to distant metastasis (DM), overall survival (OS), and locoregional control (LRC), and the corresponding log-rank test were performed. With a median follow-up of 10.5 months [mos] (range 1.0-58.7 mos), we found an improvement in PFS with TVEC and RT in the same region compared to different regions, which were 6.4 mos (95% CI, 2.4-NR mos) and 2.8 mos (95% CI, 0.7-4.4 mos), respectively; p = 0.005. There was also a significant improvement in DM when TVEC and RT were used in the same region compared to different regions: 13.8 mos (95% CI, 4.6-NR mos) and 2.8 mos (95% CI, 0.7-4.4 mos), respectively (p = 0.001). However, we found no difference in overall survival (OS) between patients who had TVEC and RT in the same region (19.0 mos, 95% confidence interval [CI], 4.1-not reached [NR] mos) and those who received treatments in different regions (18.5 mos, 95% CI, 1.0-NR mos); p = 0.366. There was no statistically significant improvement in locoregional control (LRC) in patients who had TVEC and RT in the same region was 26.0 mos (95% CI, 6.4-26.0 mos) compared to patients who received TVEC and RT in different regions (4.4 mos) (95% CI, 0.7-NR mos) (p = 0.115). No grade 3 or higher toxicities were documented in either group. Overall, there were improvements in PFS and DM when TVEC and RT were delivered to the same region of the body compared to when they were used in different regions. However, we did not find a significant difference in locoregional recurrence or OS. Future studies are needed to assess the sequence and timing of combining RT and TVEC to potentially enhance the immune response both locally and distantly.

Challenges in synergizing radiotherapy with immunotherapy to unlock the abscopal effect in metastatic NSCLC: A systematic review.

BACKGROUND: With the recent success of immunotherapy, there is a growing interest in combining radiation with immunotherapy to boost abscopal response rates. Several challenges exist in determining how to synergize these two modalities in the treatment of metastatic NSCLC. METHODS: References for this review were identified through searches of MEDLINE/PubMed and Clinicaltrials.gov databases with the search terms "abscopal", "radiation OR radiotherapy," "NSCLC", and "lung" on the index date of July 2022 from 2000-2022. This systematic review focuses primarily on clinical papers. DISCUSSION: Early work combining radiotherapy with immunotherapy show promise in unlocking the abscopal effect. Preliminary evidence suggests that radiotherapy regimens with <5 fractions and smaller fields may be superior to regimens with 15 fractions and larger fields. There does not appear to be enough evidence to draw conclusions about the optimal timing of radiotherapy in relation to immunotherapy or the optimal anatomical location of radiation to induce the abscopal effect. Several studies suggest selecting patients with a higher absolute lymphocyte count (ALC) and lower neutrophil-to-lymphocyte ratio (NLR) may help to further boost abscopal response rates. Furthermore, selecting tumors with programmed death ligand-1 (PD-L1) expression, mismatch repair deficiency, and higher tumor mutational burden may similarly achieve this goal. Lastly, additional work is needed to minimize and predict for severe toxicity associated with combination therapy.

Explainable Artificial Intelligence to Identify Dosimetric Predictors of Toxicity in Patients with Locally Advanced Non-Small Cell Lung Cancer: A Secondary Analysis of RTOG 0617.

PURPOSE: Dosimetric predictors of toxicity in patients treated with definitive chemoradiation for locally advanced non-small cell lung cancer are often identified through trial and error. This study used machine learning (ML) and explainable artificial intelligence to empirically characterize dosimetric predictors of toxicity in patients treated as part of a prospective clinical trial. METHODS AND MATERIALS: A secondary analysis of the Radiation Therapy Oncology Group (RTOG) 0617 trial was performed. Multiple ML models were trained to predict grade ≥3 pulmonary, cardiac, and esophageal toxicities using clinical and dosimetric features. Model performance was evaluated using the area under the curve (AUC). The best performing model for each toxicity was explained using the Shapley Additive Explanation (SHAP) framework; SHAP values were used to identify relevant dosimetric thresholds and were converted to odds ratios (ORs) with confidence intervals (CIs) generated using bootstrapping to obtain quantitative measures of risk. Thresholds were validated using logistic regression. RESULTS: The best-performing models for pulmonary, cardiac, and esophageal toxicities, outperforming logistic regression, were extreme gradient boosting (AUC, 0.739), random forest (AUC, 0.706), and naive Bayes (AUC, 0.721), respectively. For pulmonary toxicity, thresholds of a mean dose >18 Gy (OR, 2.467; 95% CI, 1.049-5.800; P = .038) and lung volume receiving ≥20 Gy (V20) > 37% (OR, 2.722; 95% CI, 1.034-7.163; P = .043) were identified. For esophageal toxicity, thresholds of a mean dose >34 Gy (OR, 4.006; 95% CI, 2.183-7.354; P < .001) and V20 > 37% (OR, 3.725; 95% CI, 1.308-10.603; P = .014) were identified. No significant thresholds were identified for cardiac toxicity. CONCLUSIONS: In this data set, ML approaches validated known dosimetric thresholds and outperformed logistic regression at predicting toxicity. Furthermore, using explainable artificial intelligence, clinically useful dosimetric thresholds might be identified and subsequently externally validated.

Atezolizumab plus stereotactic ablative radiotherapy for medically inoperable patients with early-stage non-small cell lung cancer: a multi-institutional phase I trial.

Stereotactic ablative radiotherapy (SABR) is a standard-of-care for medically-inoperable-early-stage non-small cell lung cancer (NSCLC). One third of patients progress and chemotherapy is rarely used in this population. We questioned if addition of the immune-checkpoint-inhibitor (ICI) atezolizumab to standard-of-care SABR can improve outcomes. We initiated a multi-institutional single-arm phase I study (NCT02599454) enrolling twenty patients with the primary endpoint of maximum tolerated dose (MTD); secondary endpoints of safety and efficacy; and exploratory mechanistic correlatives. Treatment is well tolerated and full dose atezolizumab (1200 mg) is the MTD. Efficacy signals include early responses (after 2 cycles of ICI, before initiation of SABR) in 17% of patients. Biomarkers of functional adaptive immunity, including T cell activation in the tumor and response to ex-vivo stimulation by circulating T cells, are highly predictive of benefit. These results require validation and are being tested in a phase III randomized trial.

Treated individuals who progress to action or maintenance for one behavior are more likely to make similar progress on another behavior: coaction results of a pooled data analysis of three trials.

OBJECTIVE: This study compared, in treatment and control groups, the phenomena of coaction, which is the probability that taking effective action on one behavior is related to taking effective action on a second behavior. METHODS: Pooled data from three randomized trials of Transtheoretical Model (TTM) tailored interventions (n=9461), completed in the U.S. in 1999, were analyzed to assess coaction in three behavior pairs (diet and sun protection, diet and smoking, and sun protection and smoking). Odds ratios (ORs) compared the likelihood of taking action on a second behavior compared to taking action on only one behavior. RESULTS: Across behavior pairs, at 12 and 24 months, the ORs for the treatment group were greater on an absolute basis than for the control group, with two being significant. The combined ORs at 12 and 24 months, respectively, were 1.63 and 1.85 for treatment and 1.20 and 1.10 for control. CONCLUSIONS: The results of this study with addictive, energy balance and appearance-related behaviors were consistent with results found in three studies applying TTM tailoring to energy balance behaviors. Across studies, there was more coaction within the treatment group. Future research should identify predictors of coaction in more multiple behavior change interventions.

Machine learning to refine prognostic and predictive nodal burden thresholds for post-operative radiotherapy in completely resected stage III-N2 non-small cell lung cancer.

BACKGROUND: The role of post-operative radiotherapy (PORT) for completely resected N2 non-small-cell lung cancer (NSCLC) is controversial in light of recent randomized data. We sought to utilize machine learning to identify a subset of patients who may still benefit from PORT based on extent of nodal involvement. MATERIALS/METHODS: Patients with completely resected N2 NSCLC were identified in the National Cancer Database. We trained a machine-learning based model of overall survival (OS). SHapley Additive exPlanation (SHAP) values were used to identify prognostic and predictive thresholds of number of positive lymph nodes (LNs) involved and lymph node ratio (LNR). Cox proportional hazards regression was used for confirmatory analysis. RESULTS: A total of 16,789 patients with completely resected N2 NSCLC were identified. Using the SHAP values, we identified thresholds of 3+ positive LNs and a LNR of 0.34+. On multivariate analysis, PORT was not significantly associated with OS (p = 0.111). However, on subset analysis of patients with 3+ positive LNs, PORT improved OS (HR: 0.91; 95% CI: 0.86-0.97; p = 0.002). On a separate subset analysis in patients with a LNR of 0.34+, PORT improved OS (HR: 0.90; 95% CI: 0.85-0.96; p = 0.001). Patients with 3+ positive lymph nodes had a 5-year OS of 38% with PORT compared to 31% without PORT. Patient with positive lymph node ratio 0.34+ had a 5-year OS of 38% with PORT compared to 29% without PORT. CONCLUSIONS: Patients with a high lymph node burden or lymph node ratio may present a subpopulation of patients who could benefit from PORT. To our knowledge, this is the first study to use machine learning algorithms to address this question with a large national dataset. These findings address an important question in the field of thoracic oncology and warrant further investigation in prospective studies.

Current landscape of radiation oncology in esophageal cancer: a narrative review.

Background and Objective: Esophageal cancer is an aggressive disease that is the sixth leading cause of cancer-related death worldwide. The overall treatment paradigm for esophageal cancer has changed considerably over the past decade. This narrative review aims to summarize the current landscape of radiation oncology for esophageal cancer. Methods: A systematic search of the MEDLINE/PubMed database and Clinicaltrials.gov was performed, focusing on studies published within the last 10 years. Our search queried "esophageal cancer [AND] neoadjuvant radiation" as well as "locally advanced esophageal cancer [AND] definitive radiation". Our search resulted in 298 total references. These were manually reviewed, and only 58 references were within our scope of interest ranging from 2012-2022. Key Content and Findings: For resectable esophageal cancer, neoadjuvant chemoradiation followed by surgery has been defined as the standard of care over the past decade. In patients with incomplete response to neoadjuvant chemoradiation, the benefit of immunotherapy in the adjuvant setting has recently been established. Ongoing studies are examining whether perioperative chemotherapy may be equivalent to neoadjuvant chemoradiation in resectable esophageal adenocarcinoma. For locally advanced esophageal cancer, recent studies have failed to show a benefit with radiation dose escalation in an unselected population, although the use of early positron emission tomography (PET) response to guide dose escalation is currently being studied. Other ongoing studies aiming to improve outcomes in locally advanced esophageal cancer involve using proton beam therapy to reduce toxicity and combining immunotherapy or targeted therapies with chemoradiation to amplify response. Conclusions: Recent advances in radiation oncology may continue to improve outcomes for patients with esophageal cancer.

Advances in Radiation Oncology for Pancreatic Cancer: An Updated Review.

This review aims to summarize the recent advances in radiation oncology for pancreatic cancer. A systematic search of the MEDLINE/PubMed database and Clinicaltrials.gov was performed, focusing on studies published within the last 10 years. Our search queried "locally advanced pancreatic cancer [AND] stereotactic body radiation therapy (SBRT) [OR] hypofractionation [OR] magnetic resonance guidance radiation therapy (MRgRT) [OR] proton" and "borderline resectable pancreatic cancer [AND] neoadjuvant radiation" and was limited only to prospective and retrospective studies and metanalyses. For locally advanced pancreatic cancers (LAPC), retrospective evidence supports the notion of radiation dose escalation to improve overall survival (OS). Novel methods for increasing the dose to high risk areas while avoiding dose to organs at risk (OARs) include SBRT or ablative hypofractionation using a simultaneous integrated boost (SIB) technique, MRgRT, or charged particle therapy. The use of molecularly targeted agents with radiation to improve radiosensitization has also shown promise in several prospective studies. For resectable and borderline resectable pancreatic cancers (RPC and BRPC), several randomized trials are currently underway to study whether current neoadjuvant regimens using radiation may be improved with the use of the multi-drug regimen FOLFIRINOX or immune checkpoint inhibitors.

RNA-binding protein RBM3 intrinsically suppresses lung innate lymphoid cell activation and inflammation partially through CysLT1R.

Innate lymphoid cells (ILC) promote lung inflammation in asthma through cytokine production. RNA-binding proteins (RBPs) are critical post-transcriptional regulators, although less is known about RBPs in ILC biology. Here, we demonstrate that RNA-binding motif 3 (RBM3) is highly expressed in lung ILCs and is further induced by alarmins TSLP and IL-33. Rbm3-/- and Rbm3-/-Rag2-/- mice exposed to asthma-associated Alternaria allergen develop enhanced eosinophilic lung inflammation and ILC activation. IL-33 stimulation studies in vivo and in vitro show that RBM3 suppressed lung ILC responses. Further, Rbm3-/- ILCs from bone marrow chimeric mice display increased ILC cytokine production suggesting an ILC-intrinsic suppressive function of RBM3. RNA-sequencing of Rbm3-/- lung ILCs demonstrates increased expression of type 2/17 cytokines and cysteinyl leukotriene 1 receptor (CysLT1R). Finally, Rbm3-/-Cyslt1r-/- mice show dependence on CysLT1R for accumulation of ST2+IL-17+ ILCs. Thus, RBM3 intrinsically regulates lung ILCs during allergen-induced type 2 inflammation that is partially dependent on CysLT1R.

Hallmarks of Resistance to Immune-Checkpoint Inhibitors.

Immune-checkpoint inhibitors (ICI), although revolutionary in improving long-term survival outcomes, are mostly effective in patients with immune-responsive tumors. Most patients with cancer either do not respond to ICIs at all or experience disease progression after an initial period of response. Treatment resistance to ICIs remains a major challenge and defines the biggest unmet medical need in oncology worldwide. In a collaborative workshop, thought leaders from academic, biopharma, and nonprofit sectors convened to outline a resistance framework to support and guide future immune-resistance research. Here, we explore the initial part of our effort by collating seminal discoveries through the lens of known biological processes. We highlight eight biological processes and refer to them as immune resistance nodes. We examine the seminal discoveries that define each immune resistance node and pose critical questions, which, if answered, would greatly expand our notion of immune resistance. Ultimately, the expansion and application of this work calls for the integration of multiomic high-dimensional analyses from patient-level data to produce a map of resistance phenotypes that can be utilized to guide effective drug development and improved patient outcomes.