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It is poorly understood how the tumor immune microenvironment influences disease recurrence in localized clear-cell renal cell carcinoma (ccRCC). Here we performed whole-transcriptomic profiling of 236 tumors from patients assigned to the placebo-only arm of a randomized, adjuvant clinical trial for high-risk localized ccRCC. Unbiased pathway analysis identified myeloid-derived IL6 as a key mediator. Furthermore, a novel myeloid gene signature strongly correlated with disease recurrence and overall survival on uni- and multivariate analyses and is linked to TP53 inactivation across multiple data sets. Strikingly, effector T-cell gene signatures, infiltration patterns, and exhaustion markers were not associated with disease recurrence. Targeting immunosuppressive myeloid inflammation with an adenosine A2A receptor antagonist in a novel, immunocompetent, Tp53-inactivated mouse model significantly reduced metastatic development. Our findings suggest that myeloid inflammation promotes disease recurrence in ccRCC and is targetable as well as provide a potential biomarker-based framework for the design of future immuno-oncology trials in ccRCC., Significance: Improved understanding of factors that influence metastatic development in localized ccRCC is greatly needed to aid accurate prediction of disease recurrence, clinical decision-making, and future adjuvant clinical trial design. Our analysis implicates intratumoral myeloid inflammation as a key driver of metastasis in patients and a novel immunocompetent mouse model. This article is highlighted in the In This Issue feature, p. 2221., (©2022 American Association for Cancer Research.)

Adults living with chronic respiratory diseases are at higher risk of death due to COVID-19. Our objective was to evaluate the physical and mental health symptoms among US adults living with chronic respiratory conditions. We used data of 10,760 US adults from the nationally representative COVID-19 Impact Survey. Chronic respiratory conditions were self-reported and included asthma (14.7%), chronic obstructive pulmonary disease or COPD (4.7%), and bronchitis/emphysema (11.6%). We used multivariable Poisson regression to evaluate physical health symptoms. We estimated associations of mental health symptoms using multinomial logistic regression. In multivariable models, adults with asthma were more likely to report physical symptoms including runny or stuffy nose, chest congestion, fever, and chills. In addition, adults with COPD were more likely to report several physical symptoms including fever (adjusted prevalence ratio [aPR]: 1.37, 95% confidence interval [CI]: 1.09-1.72), chills (aPR: 2.10, 95% CI: 1.67-2.64), runny or stuffy nose (aPR: 1.78, 95% CI: 1.39-2.27), chest congestion (aPR: 2.14, 95% CI: 1.74-2.61), sneezing (aPR: 1.59, 95% CI: 1.23-2.05), and muscle or body aches (aPR: 1.38, 95% CI: 1.06-1.81). Adults with chronic respiratory conditions are more likely to report physical and mental health symptoms during the COVID-19 pandemic compared to others. Providers should prioritize discussing mental health symptom management as the pandemic continues to be a public health concern in the US.