Leveraging the circadian rhythm to enhance the immunotherapy response in melanoma

The National Cancer Institute awarded Emory University $100,228 on December 1, 2026, under the Cancer Research Manpower program (CFDA 93.398) to support research elucidating the mechanisms by which circadian rhythms influence immunotherapy response in metastatic melanoma and to test novel small molecular modulators of the circadian clock to enhance immune checkpoint blockade efficacy. The research investigates circadian-directed oscillations of B cells, T cells, and dendritic cells, circadian-dependent expression of adhesion molecules on endothelial cells influencing T cell access to tumors, and potential circadian influences on T cell and dendritic cell interactions and stem-like T cell dynamics in the context of dual immune checkpoint inhibitor therapy. Work is performed at Emory University in Atlanta, Georgia, with a period of performance from December 1, 2026, through June 7, 2029.

Abstract

The prognosis for patients diagnosed with metastatic melanoma is dismal, with a 5-year survival rate of 22.5%. Survival is improved with dual immune checkpoint blockade (ICB). Yet, melanoma specific survival with dual- ICB (ΑPD-1 + αctla-4) at 10 years is still only 50%. Therefore there is a marked need to develop innovative treatment approaches to improve outcomes. Leveraging knowledge of circadian rhythms to enhance clinical responses (also known as chronomodulation) has been demonstrated in the use of vaccines and anti-neoplastic cytokine therapy but is only recently being investigated in checkpoint therapy. Our team previously published the first retrospective meta-analysis to assess time-of-day administration of immunotherapy, demonstrating that increased number of evening infusions of ICB conferred worse survival outcomes in patients with metastatic melanoma, suggesting that circadian rhythms may play a role in ICB responsiveness. This proposal will seek to fully elucidate the underlying mechanism for this observation while also testing novel small molecular modulators of the circadian clock to improve ICB responsiveness. Recent work highlights the circadian-directed oscillations of B cells, T cells, and dendritic cells (DC) in the body as well as the circadian-dependent expression of adhesion molecules on endothelial cells, which influence T cell access to the tumor. There has not been investigation on the potential circadian influence on T cell/dendritic cell interactions, structures of the immune niche, or oscillatory dynamics of stem-like T cells, all of which are critical components for a robust ICB response. There is evidence of limited improvement with timed ΑPD-1 monotherapy however no investigation of dual-ICB or other checkpoint inhibitors such as ΑLAG-3. Lastly, there has been no investigation on the pharmacologic modulation of the circadian rhythm amplitude in the context of cancer, nor with the goal of enhancing ICB responsiveness. We hypothesize that stem-like T cells and DCS form peak immune niche densities during the active phase and this CO-localization depends in part on cell autonomous circadian gene oscillation. We also hypothesize that pharmacologic amplification of the circadian clock will improve dual-ICB (ΑPD-1/ΑLAG-3) responsiveness through enhancing immune niche density and stem-like T cell differentiation. To test these hypotheses, in aim 1 we will mechanistically dissect whether the immune niche density varies throughout the circadian cycle and if this is cell-intrinsic. In aim 2 we will determine whether pharmacologic modulation of the circadian clock impacts stem-like T cell differentiation, immune niche density, and ultimately dual-ICB effectiveness. To emphasize the translational importance of this project above innovative murine models, we will investigate these concepts with melanoma patient tissue resection samples in parallel. Together, these efforts will delineate mechanisms to substantiate the chronomodulation of ICB, potentially supporting a cost-effective, low-risk, and easily-modifiable improvement to the current standard of care for melanoma and other cancer types.