||1R21CA227375-01 Interpret this number
||Roswell Park Cancer Institute Corp
||(PQ6): is Adrenergic Stress-Induced Immune Suppression at the Crossroads of Circadian Rhythm Disruption and Cancer?
ABSTRACT: In this exploratory application, two senior investigators with complementary expertise in tumor
immunology and circadian rhythm biology propose to test a novel answer to ?Provocative Question #6: How do
circadian processes affect tumor development, progression and response to therapy? We propose the
existence of a previously unexplored link between circadian rhythms and anti-tumor immune function, such that
disruption of circadian processes increases homeostatic stresses leading to increased circulating
catecholamine (norepinephrine) levels. In turn, the resultant increased ?-adrenergic receptor signaling in the
tumor microenvironment will 1) subvert on-going anti-tumor immune activity, particularly that of CD8+ T cells
and 2) reduce responsiveness to checkpoint inhibitor immunotherapy. Although this application is exploratory
in nature, it has a strong Scientific Premise since our recent findings in mouse models demonstrate that the
degree of adrenergic stress activity by the sympathetic nervous system, (already known to be influenced by
circadian processes) plays a profound role in regulating immune control of tumors, including even carcinogen-
induced tumors, as well as the efficacy of anti-PD-1 checkpoint inhibitor antibodies. Now we will test, for the
first time, the hypothesis that adrenergic-stress mediated control of anti-tumor immunity is influenced by
circadian disruption using higly relevant models of sleep disruption similar to those of humans affected by ?shift
work? or ?jet lag.?
We will address this hypothesis in two aims using well characterized murine models of circadian
disruption and tumor growth/immunotherapy already in place in the laboratories of the co-PIs. Aim 1 will test
whether circadian disruption by ?shift work? or ?jet-lag? light/dark models accelerates tumor progression, and
subverts anti-tumor immune activity, particularly that of CD8+ T cells (in which preliminary data reveals
significantly impaired metabolic programming in response to adrenergic signaling.) Aim 2 will test whether
circadian disruption influences the response to checkpoint inhibitor immunotherapy using anti-PD-1 antibodies.
These studies are predicted to identify, for the first time, the impact of circadian disruption on the
immune contexture of tumors and particularly, on ?-adrenergic receptor signaling- induced suppression of
CD8+ T cells. If successful, our studies will clarify a new mechanism-based understanding of how disrupted
circadian processes can lead to increased tumor formation and growth and impaired response to therapies.
Excitingly, these studies could also lead to new, and immediately feasible, therapeutic approaches for cancer
patients (who often experience circadian rhythm disruption) that reduce adrenergic stress (e.g., by the use of
common ?-blockers) to improve the efficacy of immunotherapy.