Eomes+T-betlow CD8+ T Cells Are Functionally Impaired and Are Associated with Poor Clinical Outcome in Patients with Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is a devastating blood cancer with poor prognosis. Immunotherapy targeting inhibitory pathways to unleash the antileukemia T-cell response is a promising strategy for the treatment of leukemia, but we must first understand the underlying molecular mechanisms. Eomesodermin (Eomes) and T-bet are both T-box transcription factors that regulate CD8+ T-cell responses in a context-specific manner. Here, we examined the role of these transcription factors in CD8+ T-cell immunity in AML patients. We report that the frequency of Eomes+T-betlow CD8+ T cells increased in newly diagnosed AML. This cell subset produced fewer cytokines and displayed reduced killing capacity, whereas depletion of Eomes by siRNA reversed these functional defects. Furthermore, Eomes bound the promoter of T-cell immunoglobulin and ITIM domain (TIGIT) and positively regulated the expression of this inhibitory receptor on patient-derived T cells. A high frequency of Eomes+T-betlow CD8+ T cells was associated with poor response to induction chemotherapy and shorter overall survival in AML patients. These findings have significant clinical implications as they not only identify a predictive and prognostic biomarker for AML, but they also provide an important target for effective leukemia therapeutics. SIGNIFICANCE: These findings reveal that a high frequency of Eomes+T-betlow CD8+ T cells predicts poor clinical outcome in AML and that targeting Eomes may provide a therapeutic benefit against AML.

Beta blocker use correlates with better overall survival in metastatic melanoma patients and improves the efficacy of immunotherapies in mice.

Immunotherapy has expanded treatment options for cancers with historically poor outcomes, yet a significant proportion of patients still fail to achieve durable clinical benefit. We defined the contribution of ß-adrenergic receptor (ßAR) signaling, a component of the stress response, on success of immunotherapy for melanoma since the use of antagonists (ß-blockers) is associated with improved clinical outcomes in some cancers. We show that metastatic melanoma patients who received immunotherapy had improved overall survival if they also received pan ß-blockers. This retrospective analysis is reinforced by results showing that ßAR blockade enhances the control of murine melanoma growth by anti-(α)PD-1 checkpoint blockade. However, this effect was most significant when ß-blocker was combined with dual αPD-1 + high dose interleukin-2 therapy and was reproduced by selective blockade of ß2ARs. These results identify a novel strategy that can be quickly introduced to potentially increase the number of patients who benefit from immune-based therapies.