Cellular senescence accumulates with age and has been shown to impact numerous physiological and pathological processes, including immune function. The role of cellular senescence in cancer is multifaceted, but the impact on immune checkpoint inhibitor response and toxicity has not been fully evaluated. In this review, we evaluate the impact of cellular senescence in various biological compartments, including the tumor, the tumor microenvironment, and the immune system, on immune checkpoint inhibitor efficacy and toxicity. We provide an overview of the impact of cellular senescence in normal and pathological contexts and examine recent studies that have connected aging and cellular senescence to immune checkpoint inhibitor treatment in both the pre-clinical and clinical contexts. Overall, senescence plays a multi-faceted, context-specific role and has been shown to modulate immune-related adverse event incidence as well as immune checkpoint inhibitor response.

Conditional gene regulation in Drosophila through binary expression systems like the LexA-LexAop system provides a superb tool for investigating gene and tissue function. To increase the availability of defined LexA enhancer trap insertions, we present molecular, genetic, and tissue expression studies of 301 novel Stan-X LexA enhancer traps derived from mobilization of the index SX4 line. This includes insertions into distinct loci on the X, II, and III chromosomes that were not previously associated with enhancer traps or targeted LexA constructs, an insertion into ptc, and seventeen insertions into natural transposons. A subset of enhancer traps was expressed in CNS neurons known to produce and secrete insulin, an essential regulator of growth, development, and metabolism. Fly lines described here were generated and characterized through studies by students and teachers in an international network of genetics classes at public, independent high schools, and universities serving a diversity of students, including those underrepresented in science. Thus, a unique partnership between secondary schools and university-based programs has produced and characterized novel resources in Drosophila, establishing instructional paradigms devoted to unscripted experimental science.

Cellular senescence accumulates with age and has been shown to impact numerous physiological and pathological processes, including immune function. The role of cellular senescence in cancer is multifaceted, but the impact on immune checkpoint inhibitor response and toxicity has not been fully evaluated. In this review, we evaluate the impact of cellular senescence in various biological compartments, including the tumor, the tumor microenvironment, and the immune system on immune checkpoint inhibitor efficacy and toxicity. We provide an overview of the impact of cellular senescence in normal and pathological contexts and examine recent studies that have connected aging and cellular senescence to immune checkpoint inhibitor treatment in both the pre-clinical and clinical contexts. Overall, senescence plays a multi-faceted, context-specific role, and has been shown to modulate immune-related adverse event incidence as well as immune checkpoint inhibitor response.

Psychological stress is well known to cause weaker immunity. Stress, through the hypothalamus-pituitary-adrenal axis, induces secretion of cortisol, which causes immune suppression. Recently, stress-induced adrenergic mechanisms have begun to be shown to mediate immune suppression. Our work here reveals a novel axis whereby stress modulates erythropoiesis via the fight-or-flight hormones, and through it, immune suppression. Elevated levels of catecholamines, acting through 2-adrenergic receptors on precursor cells in erythroid differentiation, mis-direct erythroid differentiation causing accumulation of aberrant erythroid precursor cells (EPC) in mice as well as humans. EPC suppress priming as well as expansion of the CD8+ T cell response through their effect on dendritic cells (DC); EPC trogocytose cell surface MHC I from DC, and DC exposed to EPC are less effective at T cell activation. EPC suppress tumor immunity in several models and this suppression is exacerbated during adrenergic stress. The magnitude of suppression of tumor immunity by EPC is comparable to that mediated by regulatory T cells. Higher expression of CD71, a marker for EPC, is associated with poor overall and disease free survival in many human cancers. Our results uncover a role for adrenergic signaling in erythropoiesis, and establish erythroid cells, in addition to the lymphoid and myeloid cells, as significant determinants of cancer immunity.