Editorial: Circadian Rhythms and Cancer Hallmarks: Toward Advances in Immune-Based Therapeutics, and Outcomes

Elizabeth Cash ^1* Pasquale F. Innominato ^2,3 Sandra E Sephton ⁴

• ¹ School of Medicine, University of Louisville, Louisville, United States
• ² Betsi Cadwaladr University Health Board, Bangor, United Kingdom
• ³ Warwick Crop Centre, School of Life Sciences, Faculty of Science, Engineering and Medicine, University of Warwick, Coventry, West Midlands, United Kingdom
• ⁴ Brigham Young University, Provo, Utah, United States

Circadian rhythms are the daily fluctuaBons in physiological processes that govern cell cycles and Bming of behaviors (1). Cancer hallmarks are the cellular properBes that drive the perennial growth, survival and spread of cancerous cells (2). The disrupBon of circadian rhythms can contribute to the development of some cancers by affecBng the expression of cancer hallmarks (3). Circadian rhythms also temporally regulate cellular immunity, which has important implicaBons for the burgeoning field of immune-based therapeuBcs (4). Cancer paBents exhibiBng disrupted circadian rhythms tend to suffer accelerated tumor growth and metastasis, worse anB-cancer treatment outcomes, and poorer health-related quality of life and overall survival (5). The aim of this special issue is to help elucidate the impact of circadian rhythms on processes associated with cancer and its treatments, immunotherapy in parBcular. We were pleased to accept eleven original manuscripts for this research topic.Through various approaches, several groups explored the molecular underpinnings of the connecBon between the circadian clock and cancer. Pan and colleagues have extensively reviewed the role of E-box-binding transcripBon factors in cell physiology and cancer biology, as well as their potenBal as novel therapeuBc targets. The broad group of E-box-binding transcripBon factors include two core clock genes, BMAL-1 and CLOCK. With a therapeuBc outlook, this work advances our knowledge of potenBal therapeuBc targets in cancer treatment. Zheng and colleagues focus on the latest evidence implicaBng circadian rhythm disrupBon as a causal factor in endometrial cancer and further explore the potenBal for mediaBon of these effects by non-coding RNAs. New research implicaBng irregular expression of circadian-linked ncRNAs in endometrial cancer cells is described, which may have implicaBons for future targeted therapeuBc strategies. Meng and colleagues deployed a Mendelian randomizaBon analyBcal approach to large internaBonal databases to explore the impact of 5 geneBcally independent circadian features on colorectal cancer risk. Strikingly, they observed that an individual chronotype might significantly contribute to the lifeBme risk of developing colorectal cancer. Peng and colleagues offer a mulB-gene prognosBc model developed using circadian genes that demonstrated predicBve performance for gynecologic cancer prognosis. This bioinformaBcs approach -validated in human data -also provides insights into potenBal immunotherapy targets by elucidaBng immune signaling pathways associated with high-risk circadian gene profiles.Several groups criBqued or provided data implicaBng the importance of sleep and circadian influences on cancer risk and outcomes. Gouldthorpe and colleagues, reviewing studies that incorporate objecBve circadian rhythm measurement, provide a useful compendium of the diverse indices used to summarize circadian endocrine data, acBgraphy data, and sleep-wake cycles, with an urgent call for standardizaBon of measurement. The need for standardizaBon is also highlighted by Jagielo and colleagues, who find that both corBsol dysregulaBon and abnormal rest-acBvity rhythms are clearly linked with psychological comorbidiBes in advanced cancer paBents, such as pain, faBgue, nausea, vomiBng, and cachexia. Promising data on chronomodulated chemotherapy and circadian-targeBng behavioral intervenBons are discussed.Nehnin and colleagues highlight a new and promising approach to treatment that regulated the circadian funcBon of gliomas, poinBng to the importance of targeBng circadian regulaBon in the tumor microenvironment, as well as the disBnct need for research in pediatric cancers. Burch and colleagues explored the associaBon between formally diagnosed sleep disorders and cancer occurrence in a robust sample of Veterans. They idenBfy an opBmal sleep duraBon for protecBon against oncogenesis: elevated lifeBme cancer risk was noted among those who slept on average less than 6, or more than 8, hours nightly. InteresBngly, greater severity and longer duraBon of sleep disorders both displayed an impact on cancer incidence. Finally, Cash and colleagues report on pilot data that opens avenues for further exploraBon of the links between diurnal corBsol expression, head and neck cancer progression, and the potenBal role of inflammaBon. They emphasize the importance of mulB-day corBsol sampling. Together, these data suggest that by recognizing the Bming of treatment in relaBon to corBsol levels, clinicians could opBmize treatment schedules to align with paBents' circadian rhythms, potenBally enhancing therapeuBc outcomes.Through their unique mechanism of acBon, immune checkpoint inhibitors are influenced by host physiology, including circadian rhythms. Two mini reviews summarize the growing evidence of interacBons between host physiology and checkpoint inhibitors. In the first, Hughes and colleagues have criBcally revised how light exposure, physical exercise and diet, and notably their respecBve Bmings across 24 hours, can impact immunotherapy efficacy in paBents with cancer. Balachandran and colleagues review important emerging data suggesBng that sleep disturbance is inversely correlated with tumor responsiveness to immunotherapy. Nascent links to the microbiome as a mechanism for these effects are considered along with remaining unanswered quesBons, such as whether these interconnecBons can be exploited to improve paBent response to immunotherapy. These reviews lay the foundaBons for novel therapeuBc avenues with potenBal circadian-based lifestyle modificaBons that could be implemented to manipulate cancer immune responsiveness and maximize the benefit from immunotherapy (6).This issue highlights circadian effects on tumor outcomes from two perspecBves: that of the host (cancer paBent) and that of the tumor and its associated microenvironment. These two perspecBves offer unique research quesBons. To improve immunotherapy outcomes, we must establish the mechanisms of circadian effects on tumor growth and acquisiBon of cancer hallmarks. This line of inquiry can lead to behavioral and pharmacotherapeuBc intervenBons to increase immunotherapy efficacy.Research must elucidate molecular clock funcBon in tumors, and how tumors disrupt circadian rhythmicity within their microenvironments. Host and tumor circadian disrupBon is rarely studied within the same organism. Such data will inform on bidirecBonal effects in host--tumor circadian relaBonships: e.g., do paBents with disrupted rhythms have tumors that suppress or promote their own circadian genes? Research imperaBves include establishing the temporal precedence of circadian disrupBon in the development of cancer, whether bidirecBonal pathways of circadian regulaBon exist between host and tumor, and a focus on circadian rhythm disorders across malignant and nonmalignant clinical groups. StandardizaBon of protocols assessing popular measures (e.g., corBsol, melatonin) is needed in addiBon to pursuing lesserstudied measures (e.g., core body temperature, pupillometry, blood pressure dipping). A noted area ripe for inquiry regards the effects of sleep and circadian disrupBon in cancer treatment efficacy (e.g., immunotherapy). We should leverage biorepositories and epidemiological-level circadian data. Despite the need for more research, clear clinical implicaBons include the need for healthcare providers to assess and treat sleep and circadian disrupBon among cancer paBents. While new technologies for measuring, for example, clock gene expression, are promising, many protocols remain potenBally burdensome to paBents. There remains an urgent need for translaBon of circadian measurement into clinical cancer senngs to inform individualized clinical intervenBons.