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Abstract Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via β2-adrenergic receptor (β2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using β2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.

Abstract Introduction Peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) is a rare, highly heterogeneous group of mature T‐cell neoplasms that historically has been associated with poor outcomes. We sought to investigate the influence of primary disease site on PTCL‐NOS outcomes using a large national cancer registry. Methods Baseline clinical and demographic data including primary organ of involvement and Ann Arbor disease stage were extracted from the SEER database. Patients were grouped into nine organ system groups and compared to nodal disease acting as a control. Cox regression models were utilized for adjusted survival analyses. Results A total of 3095 patients were identified in the SEER database and included in the final analysis. The median age was 61 and a majority of patients were male (60%) and identified as non‐Hispanic white (68%). A plurality of patients had stage IV disease (32%). Lymph nodes and spleen were the most common primary disease sites (67%), while central nervous system was the least common (1%). Patients with early‐stage PTCL‐NOS of the gastrointestinal/genitourinary systems had worse overall survival [HR = 1.97 (1.50–2.59); p

Introduction: Renal cell carcinoma (RCC) with sarcomatoid component carries a poor prognosis. Immune checkpoint inhibitors (CPIs) have been approved for the treatment of metastatic RCC, but their efficacy in patients with sarcomatoid component is not known. Materials and Methods: We conducted a retrospective chart review of 30 consecutive patients at our center who were treated for metastatic RCC with sarcomatoid component. Results: Ten patients were treated with CPI group while 20 patients were in No-CPI group. There were no significant differences in age, sex, race, and stage at diagnosis between the two groups. After a median follow-up of 35 months, 3 of 10 patients in CPI arm and 5 of 20 patients in No-CPI group were alive. The median overall survival was 33.8 m in immunotherapy group compared to 8.8 m in nonimmunotherapy group (p = .001). Discussion: In our experience, CPI therapy resulted in better outcomes compared to traditional therapy with molecular-targeted agents or chemotherapy in these patients.