Association of bronchial disease on CT imaging and clinical definitions of chronic bronchitis in a single-center COPD phenotyping study.

INTRODUCTION: Chronic Bronchitis (CB) represents a phenotype of chronic obstructive pulmonary disease (COPD). While several definitions have been used for diagnosis, the relationship between clinical definitions and radiologic assessment of bronchial disease (BD) has not been well studied. The aim of this study was to evaluate the relationship between three clinical definitions of CB and radiographic findings of BD in spirometry-defined COPD patients. METHODS: A cross-sectional analysis was performed from a COPD phenotyping study. It was a prospective observational cohort. Participants had spirometry-defined COPD and available chest CT imaging. Comparison between CB definitions, Medical Research Council (CBMRC), St. George's Respiratory Questionnaire (CBSGRQ), COPD Assessment Test (CBCAT) and CT findings were performed using Cohen's Kappa, univariate and multivariate logistic regressions. RESULTS: Of 112 participants, 83 met inclusion criteria. Demographics included age of 70.1 ± 7.0 years old, predominantly male (59.0 %), 45.8 ± 30.8 pack-year history, 21.7 % actively smoking, and mean FEV1 61.5 ± 21.1 %. With MRC, SGRQ and CAT definitions, 22.9 %, 36.6 % and 28.0 % had CB, respectively. BD was more often present in CB compared to non-CB patients; however, it did not have a statistically significant relationship between any of the CB definitions. CBSGRQ had better agreement with radiographically assessed BD compared to the other two definitions. CONCLUSION: Identification of BD on CT was associated with the diagnoses of CB. However, agreement between imaging and definitions were not significant, suggesting radiologic findings of BD and criteria defining CB may not identify the same COPD phenotype. Research to standardize imaging and clinical methods is needed for more objective identification of COPD phenotypes.

NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustion.

The progressive decline of CD8 T cell effector function-also known as terminal exhaustion-is a major contributor to immune evasion in cancer. Yet, the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here, we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Texterm) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1+TIM-3+) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically, we identify PTGIR, a receptor for the circulating eicosanoid prostacyclin, as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-γ and granzyme production) to chronic infection and cancer. Together, these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states.

Physical exercise in liver diseases.

Liver diseases contribute to ~2 million deaths each year and account for 4% of all deaths globally. Despite various treatment options, the management of liver diseases remains challenging. Physical exercise is a promising nonpharmacological approach to maintain and restore homeostasis and effectively prevent and mitigate liver diseases. In this review, we delve into the mechanisms of physical exercise in preventing and treating liver diseases, highlighting its effects on improving insulin sensitivity, regulating lipid homeostasis, and modulating immune function. In addition, we evaluate the impact of physical exercise on various liver diseases, including liver ischemia/reperfusion injury, cardiogenic liver disease, metabolic dysfunction-associated steatotic liver disease, portal hypertension, cirrhosis, and liver cancer. In conclusion, the review underscores the effectiveness of physical exercise as a beneficial intervention in combating liver diseases.

Study Protocol for a Randomized Controlled Trial of Low Intensity Shockwave Therapy for the Treatment of Post-Radical Prostatectomy Erectile Dysfunction: "SHARP-ED TRIAL".

Introduction: Erectile Dysfunction (ED) is a common challenge post Radical Prostatectomy (RALP), affecting men's sexual health after undergoing definitive cancer therapy. Despite employing nerve-sparing techniques, ED remains a prevalent issue in this population. Studies indicate that approximately 70%-85% of men experience varying degrees of ED following RALP. The existing treatment landscape for post-RALP-ED presents limitations, and a discernible knowledge gap persists. To address this, our study aims to investigate the efficacy of Shockwave Therapy (SWT) as a potential intervention for managing ED after RALP. Methods: This prospective, randomized, sham-controlled clinical trial aims to recruit 189 eligible patients post-RP and assess the effects of SWT. Comprehensive screening, including medical history, physical examinations, and biochemical evaluations, will be conducted to confirm eligibility. The intervention involves utilizing a device to administer focal shockwaves targeted at cavernosal tissue. Safety measures include continuous monitoring for adverse events and rigorous reporting protocols. The primary endpoint assesses changes in participants' ability to engage in penetrative intercourse from baseline to study completion, while secondary endpoints encompass various measures of erectile function, including questionnaire-based assessments, ultrasound parameters, and clinical outcomes. Results: Statistical analysis, encompassing ANOVA for continuous variables and Fisher's exact test for categorical ones, will evaluate demographic characteristics, baseline data, and primary as well as secondary outcomes for statistical significance. Detailed analysis of trends, subgroup comparisons, and treatment effects will provide a comprehensive understanding of the impact of SWT on post-RP ED. Conclusion: This study protocol represents a rigorous investigation into the potential therapeutic role of SWT in managing post-RP ED. The outcomes from this study aim to contribute valuable insights into the efficacy, safety, and potential improvements in erectile function following SWT, providing significant guidance for future interventions aimed at addressing this challenging condition affecting men's health and quality of life.

Optimizing Morbidity in Unplanned Soft Tissue Sarcoma Excisions: Should We Skip the Reconstructive Ladder?

INTRODUCTION: Soft tissue sarcomas (STSs) are rare and diverse primary malignant tumors that comprise approximately 1% of all malignancies. Misdiagnoses and unplanned excisions of STSs are common due to the tumor's rarity, leading to secondary tumor bed excisions (TBEs). Reconstructive outcomes for TBEs remain poorly understood, prompting this study to address the knowledge gap and inform preoperative discussions. METHODS: This was a retrospective cohort study of patients who underwent STS excisions at a quaternary cancer center. Patients were categorized into mass excision (ME) and TBE groups. Reconstructive approaches were divided into simple (primary closure, complex repair, skin grafts, local flaps) and advanced (pedicled or free flaps). The groups were compared for postoperative outcomes, including complications, recurrence, and death. RESULTS: When simple reconstructive techniques were used, TBEs exhibited higher rates of overall and major complications, whereas MEs had higher rates of overall and minor complications. Intergroup analysis revealed that with simple reconstruction, rates of overall and major complications were higher in TBEs than in MEs, and rates of minor complications were higher in MEs than in TBEs. Regression analyses revealed that simple reconstruction of TBEs had 90% and 180% higher odds of major complications and reoperation compared to simple reconstruction of MEs (P < 0.05). CONCLUSION: TBEs, despite their smaller size, exhibited a heightened susceptibility to overall and major complications, challenging the notion that simpler techniques suffice in these cases. Our findings encourage the consideration of advanced reconstructive techniques for TBEs that may seem amenable to simple reconstructive techniques.

13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.

Infusion of 13C-labeled metabolites provides a gold standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of 13C-labeled metabolites (glucose, glutamine, and acetate) in Listeria monocytogenes-infected mice, we demonstrate that CD8 T effector (Teff) cells use metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily toward nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support adenosine triphosphate and de novo pyrimidine synthesis. In addition, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo. CD8 Teff cells change fuel preference over the course of infection, switching from glutamine- to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with CD8 Teff cell function in vivo.

When to ditch the ladder and take the elevator: The Anderson SArcoma Risk of Complications (A-SARC) score to guide reconstructive decision-making in extremity soft tissue sarcoma patients.

BACKGROUND: The reconstructive ladder relies mostly on defect size and depth to determine reconstructive technique, however, in actuality, many more variables ultimately inform reconstructive decision making, especially regarding extremity soft tissue sarcoma (eSTS) defects. The purpose of this study was to describe eSTS patients who will most optimally benefit from an advanced method of reconstruction (defined as a pedicled regional flap or free flap) and to create a simple risk assessment scale that can be employed in clinical practice. STUDY DESIGN: A single-institution retrospective cohort study examined patients undergoing resection of soft tissue sarcoma affecting the upper or lower extremities between 2016 and 2021. We categorized patients who required a pedicled or free flap as having had advanced reconstruction, and all other techniques were considered simple reconstruction. A regression was used to create a risk scale to guide reconstructive decision-making. RESULTS: The following variables were identified as independent predictors of complications and used to create our risk scale: lower extremity tumor location, preoperative radiotherapy, tumor bed excision, male sex, hypertension, and tumor volume. Intermediate and high-risk patients reconstructed using simple techniques had significantly greater overall complication rates compared to those reconstructed with advanced techniques. Major complications were significantly greater in low-risk patients reconstructed with advanced techniques. CONCLUSIONS: To minimize postoperative wound complications, low-risk patients should receive simple methods of reconstruction, whereas high-risk patients should be reconstructed using advanced techniques.

Acod1 expression in cancer cells promotes immune evasion through the generation of inhibitory peptides.

Targeting programmed cell death protein 1 (PD-1) is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites in the tumor microenvironment. Here, we find that αPD-1-resistant cancer cells produce abundant itaconate (ITA) due to enhanced levels of aconitate decarboxylase (Acod1). Acod1 has an important role in the resistance to αPD-1, as decreasing Acod1 levels in αPD-1-resistant cancer cells can sensitize tumors to αPD-1 therapy. Mechanistically, cancer cells with high Acod1 inhibit the proliferation of naive CD8+ T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8+ T cell proliferation is not dependent on the secretion of ITA but is instead a consequence of the release of small inhibitory peptides. Our study suggests that strategies to counter the activity of Acod1 in cancer cells may sensitize tumors to ICB therapy.

A primer on the restorative therapies for erectile dysfunction: a narrative review.

INTRODUCTION: Erectile dysfunction (ED) is a common condition that affects millions worldwide. Patients and urologists alike are seeking alternative therapies that can provide long-lasting results in the treatment of ED. This review provides a comprehensive overview of restorative treatments available for ED, such as platelet-rich plasma, stem cell therapy, and shockwave therapy. OBJECTIVE: The aim of this narrative review is to provide a primer for urologists and general practitioners on the basics of implementing ED restorative therapies in their practice. METHODS: The PubMed, MEDLINE, and Google Scholar databases were searched for articles in the English language through August 31, 2023, that included key terms such as "erectile dysfunction," "restorative therapy," "shockwave therapy," "platelet-rich plasma," "stem cell therapy," and "stromal vascular fraction." Reference lists of selected studies were manually reviewed to find articles not identified by the initial database search. RESULTS: Shockwave therapy has demonstrated effectiveness in treating ED, with devices like the Medispec ED1000 and Storz Duolith showing statistically significant improvements in patient scores for International Index of Erectile Function (IIEF)-Erectile Function scores in clinical trials. In reported studies of platelet-rich plasma injections, a substantial percentage of patients reached a minimal clinically important difference in the IIEF-Erectile Function scale after treatment. Studies of ED treatment with stem cell therapy, while limited and with small sample sizes, have demonstrated encouraging improvements in patient scores for the abridged 5-item version of the IIEF after treatment. CONCLUSION: Shockwave, platelet-rich plasma, and stem cell therapies are important, novel, noninvasive restorative treatments for ED that can provide relief for patients wishing to avoid a more invasive approach. While these therapies have shown promising results in clinical trials, more research is required to establish them as standardized and efficacious options in the management of ED.

Sarcoma Size and Limb Dimensions Predict Complications, Recurrence, and Death in Patients with Soft Tissue Sarcoma in the Thigh: A Multidimensional Analysis.

BACKGROUND: Limb-sparing resections of thigh soft tissue sarcomas (STSs) can result in adverse outcomes. Identifying preoperative predictors for wound healing complications, tumor recurrence, and mortality is crucial for informed reconstructive decision-making. We hypothesized that preoperative measurements of thigh and tumor dimensions could serve as reliable indicators for postoperative complications, recurrence, and death. PATIENTS AND METHODS: In this retrospective cohort study conducted from March 2016 to December 2021, we analyzed patients undergoing thigh STS excisions followed by reconstruction. Preoperative magnetic resonance imaging or computed tomography scans provided necessary thigh and tumor dimensions. Univariate and multivariate regression assessed relationships between these dimensions and postoperative outcomes, including complications, recurrence, and death. RESULTS: Upon the analysis of 123 thighs, we found thigh width to be highly predictive of postoperative complications, even surpassing body mass index (BMI) and retaining significance in multivariate regression [odds ratio (OR) 1.19; 95% CI 1.03-1.39; p = 0.03]. Sarcoma-to-thigh width and thickness ratios predicted STS recurrence, with the thickness ratio retaining significance in multivariate regression (OR 1.03; 95% CI 1.001-1.05; p = 0.041). Notably, greater thigh thickness was independently protective against mortality in multivariate analysis (OR 0.80; 95% CI 0.65-0.98; p = 0.030). CONCLUSIONS: Thigh width outperformed BMI in association with postoperative complications. This may create an opportunity for intervention, where weight loss can play a role during the neoadjuvant therapy period to potentially reduce complications. Sarcoma-to-thigh width and thickness ratios, particularly the latter, hold substantial predictive value in terms of STS recurrence. Moreover, thigh thickness is an independent predictor of survival.

High Community-Level Social Vulnerability is Associated with Worse Recurrence-Free Survival (RFS) After Resection of Extremity and Truncal Soft Tissue Sarcoma.

BACKGROUND: Although social vulnerability has been associated with worse postoperative and oncologic outcomes in other cancer types, these effects have not been characterized in patients with soft tissue sarcoma. This study evaluated the association of social vulnerability and oncologic outcomes. METHODS: The authors conducted a single-institution cohort study of adult patients with primary and locally recurrent extremity or truncal soft tissue sarcoma undergoing resection between January 2016 and December 2021. The social vulnerability index (SVI) was measured on a low (SVI 1-39%, least vulnerable) to high (60-100%, most vulnerable) SVI scale. The association of SVI with overall survival (OS) and recurrence-free survival (RFS) was evaluated by Kaplan-Meier analysis and Cox proportional hazard regression. RESULTS: The study identified 577 patients. The median SVI was 44 (interquartile range [IQR], 19-67), with 195 patients categorized as high SVI and 265 patients as low SVI. The median age, tumor size, histologic subtype, grade, comorbidities, stage, follow-up time, and perioperative chemotherapy and radiation utilization were similar between the high and low SVI cohorts. The patients with high SVI had worse OS (p = 0.07) and RFS (p = 0.016) than the patients with low SVI. High SVI was independently associated with shorter RFS in the multivariate analysis (hazard ratio, 1.64; 95% confidence interval, 1.06-2.54) but not with OS (HR, 1.47; 95% CI 0.84-2.56). CONCLUSION: High community-level social vulnerability appears to be independently associated with worse RFS for patients undergoing resection of extremity and truncal soft tissue sarcoma. The effect of patient and community-level social risk factors should be considered in the treatment of patients with extremity sarcoma.

A randomized, non-comparative phase 2 study of neoadjuvant immune-checkpoint blockade in retroperitoneal dedifferentiated liposarcoma and extremity/truncal undifferentiated pleomorphic sarcoma.

Based on the demonstrated clinical activity of immune-checkpoint blockade (ICB) in advanced dedifferentiated liposarcoma (DDLPS) and undifferentiated pleomorphic sarcoma (UPS), we conducted a randomized, non-comparative phase 2 trial ( NCT03307616 ) of neoadjuvant nivolumab or nivolumab/ipilimumab in patients with resectable retroperitoneal DDLPS (n = 17) and extremity/truncal UPS (+ concurrent nivolumab/radiation therapy; n = 10). The primary end point of pathologic response (percent hyalinization) was a median of 8.8% in DDLPS and 89% in UPS. Secondary end points were the changes in immune infiltrate, radiographic response, 12- and 24-month relapse-free survival and overall survival. Lower densities of regulatory T cells before treatment were associated with a major pathologic response (hyalinization > 30%). Tumor infiltration by B cells was increased following neoadjuvant treatment and was associated with overall survival in DDLPS. B cell infiltration was associated with higher densities of regulatory T cells before treatment, which was lost upon ICB treatment. Our data demonstrate that neoadjuvant ICB is associated with complex immune changes within the tumor microenvironment in DDLPS and UPS and that neoadjuvant ICB with concurrent radiotherapy has significant efficacy in UPS.

Identifying risk factors and analyzing reconstructive outcomes in patients with lower-extremity soft-tissue sarcoma.

PURPOSE: Reconstructing defects after resecting soft-tissue sarcoma (STS) can be challenging. The aim of this retrospective study was to analyze the reconstructive outcomes and identify the potential risk factors in patients undergoing reconstruction after excision of lower-extremity STS. METHODS: Patients with lower-extremity STS were included. This database was compiled of patients from a single, large National Cancer Institute-accredited academic hospital. In total, 302 patients were included between January 2016 to January 2022. Univariate and multivariate analyses were performed to calculate odds ratios (ORs) for developing complications for each patient and surgical characteristic. RESULTS: The following factors were independent predictors of any complication: benign pulmonary disease (OR = 4.2; p = 0.02), preoperative radiotherapy (RT; OR = 2.5; p = 0.047), a tumor in the medial thigh (OR = 1.9; p = 0.03), body mass index (BMI) > 30 kg/m2 (OR = 1.05; p = 0.037), and full-thickness skin graft (OR = 5.4; p = 0.01). In the preoperative RT subgroup, reconstructing a defect via undermining and layered closure alone was an independent predictor of dehiscence (OR = 2.1; p = 0.02) and seroma (OR = 3.1; p = 0.02), whereas pedicled flaps (OR = 0.08; p = 0.001) and free flaps (OR = 0.05; p = 0.001) were independent protectors against any complication. CONCLUSION: Information derived from this analysis will assist with accurate preoperative patient counseling, which is crucial for informed decision-making and expectation management in lower-extremity STS. BMI and pulmonary function should be optimized to the extent possible to reduce postoperative complications. Patients treated preoperatively with RT should be reconstructed with a pedicled or free flap to optimize recovery.

Development of a Novel Comprehensive Hepatocellular Carcinoma Outcome Prognostic Scoring System With Integration of Imaging Features.

BACKGROUND: Accurate prognostic stratification of hepatocellular carcinoma (HCC) is vital for clinical trial enrollment and treatment allocation. Multiple scoring systems have been created to predict patient survival, but no standardized scoring systems account for radiologic tumor features. We sought to create a generalizable scoring system for HCC which incorporates standardized radiologic tumor features and more accurately predicts overall survival (OS) than established systems. METHODS: Clinicopathologic parameters were collected from a prospectively collected cohort of patients with HCC treated at a single institution. Imaging studies were evaluated for tumor characteristics. Patients were randomly divided into a training set for identification of covariates that impacted OS and a validation set. Cox models were used to determine the association of various factors with OS and a scoring system was created. RESULTS: We identified 383 patients with HCC with imaging and survival outcomes, n = 255 in the training set and 128 in the validation cohort. Factors associated with OS on multivariate analysis included: tumor margin appearance on CT or MRI (hazard ratio [HR] 1.37, 95% CI, 1.01-1.88) with infiltrative margins portending worse outcomes than encapsulated margins, massive tumor morphology (HR 1.64, 95% CI, 1.06-2.54); >2 lesions (HR 2.06, 95% CI, 1.46-2.88), Child-Turcotte-Pugh class C (HR 3.7, 95% CI, 2.23-6.16), and portal vein thrombus (HR 2.41, 95% CI, 1.71-3.39). A new scoring system was developed and more predictive of OS than other well-established systems. CONCLUSIONS: Incorporation of standardized imaging characteristics to established clinical and lab predictors of outcome resulted in an improved predictive scoring system for patients with HCC.

High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling.

Oxytocin-expressing paraventricular hypothalamic neurons (PVNOT neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVNOT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVNOT neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on a chow diet. Notably, exposing wild-type mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity toward CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVNOT neurons. Restoring OT pathways in diet-induced obese (DIO) mice via chemogenetics or polypharmacology sufficiently re-establishes CCK's anorexigenic effects. Last, by single-cell profiling, we identify a specialized PVNOT neuronal subpopulation with increased κ-opioid signaling under an HFHS diet, which restrains their CCK-evoked activation. In sum, we document a (patho)mechanism by which PVNOT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.

Primary tumor site for localized Merkel cell carcinoma drives different management strategies without impacting oncologic outcomes.

BACKGROUND AND PURPOSE: Clinically localized Merkel cell carcinoma (MCC) has been associated with high rates of disease relapse. This study examines how primary tumor anatomic site drives patterns of care and outcomes in a large cohort treated in the contemporary era. MATERIALS AND METHODS: Patterns of care and associated outcomes were evaluated for clinically Stage I-II MCC patients treated at our institution with adjuvant radiation therapy (RT) to the primary site and/or regional nodal basin as a component of their curative intent therapy between 2014-2021. RESULTS: Of 80 patients who met inclusion criteria, the primary tumor anatomic site was head and neck (HN) for 42 (53%) and non-head and neck (NHN) for 38 (47%). Primary tumor risk factors were similar between cohorts. Fewer patients with HN tumors had wide local excision (WLE; HN-81% vs. NHN-100% p < 0.01). Of those undergoing WLE, patients with HN tumors received higher dose adjuvant RT (>50 Gy: HN-70% vs. NHN-8%; p < 0.01). Patients with HN tumors were less likely to undergo sentinel lymph node biopsy (HN-62%vs. NHN-100%; p < 0.01) and more likely to have elective nodal RT (HN-48% vs. NHN-0%). Despite varying management strategies, there was no significant difference in local recurrence-free survival (3-yr LRFS HN-94% vs. NHN-94%; p = 0.97), nodal recurrence-free survival (3-yr NRFS HN-89% vs. NHN-85%; p = 0.71) or overall recurrence-free survival (3-yr RFS 73% HN vs. 80% NHN; p = 0.44). CONCLUSIONS: Among patients with primary MCC who had RT as a component of their initial treatment strategy, anatomically-driven heterogeneous treatment approaches were associated with equally excellent locoregional disease control.

Acod1 Expression in Cancer Cells Promotes Immune Evasion through the Generation of Inhibitory Peptides.

Targeting PD-1 is an important component of many immune checkpoint blockade (ICB) therapeutic approaches. However, ICB is not an efficacious strategy in a variety of cancer types, in part due to immunosuppressive metabolites in the tumor microenvironment (TME). Here, we find that αPD-1-resistant cancer cells produce abundant itaconate (ITA) due to enhanced levels of aconitate decarboxylase (Acod1). Acod1 has an important role in the resistance to αPD-1, as decreasing Acod1 levels in αPD-1 resistant cancer cells can sensitize tumors to αPD-1 therapy. Mechanistically, cancer cells with high Acod1 inhibit the proliferation of naïve CD8+ T cells through the secretion of inhibitory factors. Surprisingly, inhibition of CD8+ T cell proliferation is not dependent on secretion of ITA, but is instead a consequence of the release of small inhibitory peptides. Our study suggests that strategies to counter the activity of Acod1 in cancer cells may sensitize tumors to ICB therapy.