Poster Presentation Asia-Pacific Vaccine and Immunotherapy Congress 2023

Influence of melanoma diagnosis on the circadian variation of lymphocytes (#102)

Yixuan He 1 , Michael C. Lowe 2 , Melinda L. Yushak 3 , David H. Lawson 3 , Chrystal M. Paulos 2 , Zachary S. Buchwald 4 , Chirag J. Patel 5 , David C. Qian 4
  1. Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States
  2. Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, United States
  3. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia, United States
  4. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, Georgia, United States
  5. Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, United States

Introduction: Lymphocytes are the main effector cells that promote responsiveness to cancer immunotherapy. We were the first to show that earlier time-of-day immunotherapy for metastatic melanoma is associated with longer progression-free and overall survival1, potentially due to better synchronization of adaptive immune stimulation and oscillating T lymphocytes in the lymphovascular space2–4. In this study, we examined time-of-day variation of circulating lymphocytes in patients with melanoma to guide treatment times for a planned randomized controlled trial (RCT) of earlier vs. later infusion of immunotherapy.

Methods: In the UK Biobank5, we identified participants at enrollment who had (A) an active diagnosis of melanoma, (B) overlapping comorbidities with group A but no diagnosis of melanoma, or (C) no documented diagnoses, using linked ICD9/10 codes. For each group, time-of-day of blood collection at enrollment and corresponding absolute lymphocyte count (ALC) were fitted to cosinor models to detect differences in amplitude, acrophase, and midline-estimating statistic of rhythm (MESOR) for daily ALC variation.

Results: There were 329,710 subjects (Table6) who met study eligibility. Compared to healthy subjects in group C, those in groups A and B were more likely to be female, older, obese, former smokers, and members of lower income households (P<0.0001). Sleep duration and temporal distributions of blood collection did not differ among groups (P>0.05). While estimated amplitudes and times of peak ALC (2:30–2:40) were similar across groups (P>0.05), subjects with melanoma had higher MESOR of ALC than healthy subjects (2020 vs. 1960/μL, P=0.019).

Conclusions: Using spot measurements from a large population-based cohort study, we replicated the rhythmicity of circulating lymphocytes in healthy individuals demonstrated by previous serial blood measurements7. Moreover, phase and amplitude of lymphocyte oscillation appear unaffected by melanoma diagnosis. For patients with melanoma, these findings support the design of RCTs that test immunotherapy administration during the early morning vs. late afternoon.

  1. Qian DC, Kleber T, Brammer B, et al. Effect of immunotherapy time-of-day infusion on overall survival among patients with advanced melanoma in the USA (MEMOIR): a propensity score-matched analysis of a single-centre, longitudinal study. Lancet Oncol 2021; 22: 1777–1786.
  2. Wang C, Barnoud C, Cenerenti M, et al. Dendritic cells direct circadian anti-tumour immune responses. Nature 2023; 614: 136–143.
  3. Gabriel CH, Kramer A. Time of day shapes the success of a cancer treatment. Nature 2023; 614: 41–42.
  4. Ince LM, Barnoud C, Lutes LK, et al. Influence of circadian clocks on adaptive immunity and vaccination responses. Nat Commun 2023; 14: 476.
  5. Bycroft C, Freeman C, Petkova D, et al. The UK Biobank resource with deep phenotyping and genomic data. Nature 2018; 562: 203–209.
  6. Table. Subject characteristics (https://bit.ly/3YPkQEJ)
  7. Dimitrov S, Benedict C, Heutling D, et al. Cortisol and epinephrine control opposing circadian rhythms in T cell subsets. Blood 2009; 113: 5134–5143.