Forrest Lee Baker

Interests

Research

Exercise Immunology, Cancer Immunotherapy, Pediatric Oncology, Gamma-Delta T-cells, Exercise Physiology, and Athlete Health

Teaching

Exercise Physiology

Courses

Scholarly Contributions

Chapters

• Baker, F. L. (2018). Aging Immunity and the Impact of Physical Exercise. In Handbook of Immunosenescence: Basic Understanding and Clinical Implications.

Journals/Publications

• Baker, F. L., Smith, K. A., Mylabathula, P. L., Zúñiga, T. M., Diak, D. M., Batatinha, H., Niemiro, G. M., Seckeler, M. D., Pedlar, C. R., O'Connor, D. P., Colombo, J., Katsanis, E., & Simpson, R. J. (2024). Exercise-induced β2-adrenergic Receptor Activation Enhances the Antileukemic Activity of Expanded γδ T-Cells via DNAM-1 Upregulation and PVR/Nectin-2 Recognition. Cancer research communications, 4(5), 1253-1267.
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  Exercise mobilizes cytotoxic lymphocytes to blood which may allow superior cell products to be harvested and manufactured for cancer therapy. Gamma-Delta (γδ) T-cells have shown promise for treating solid tumors, but there is a need to increase their potency against hematologic malignancies. Here, we show that human γδ T-cells mobilized to blood in response to just 20 minutes of graded exercise have surface phenotypes and transcriptomic profiles associated with cytotoxicity, adhesion, migration, and cytokine signaling. Following 14 days ex vivo expansion with zoledronic acid and IL2, exercise mobilized γδ T-cells had surface phenotypes and transcriptomic profiles associated with enhanced effector functions and demonstrated superior cytotoxic activity against multiple hematologic tumors in vitro and in vivo in leukemia-bearing xenogeneic mice. Infusing humans with the β1+β2-agonist isoproterenol and administering β1 or β1+β2 antagonists prior to exercise revealed these effects to be β2-adrenergic receptor (AR) dependent. Antibody blocking of DNAM-1 on expanded γδ T-cells, as well as the DNAM-1 ligands PVR and Nectin-2 on leukemic targets, abolished the enhanced antileukemic effects of exercise. These findings provide a mechanistic link between exercise, β2-AR activation, and the manufacture of superior γδ T-cell products for adoptive cell therapy against hematologic malignancies.
• Batatinha, H., Niemiro, G. M., Pena, N., Hoskin, G., Mylabathula, P., Baker, F., Zuniga, T., Smith, K., Diak, D., Seckeler, M., Katsanis, E., & Simpson, R. (2024). Abstract LB066: Acute systemic beta-adrenergic receptor activation to improve graft composition and outcomes in hematopoietic stem cell transplantation. Cancer Research, 84(7_Supplement), LB066-LB066. doi:10.1158/1538-7445.am2024-lb066
• Smith, K. A., Zúñiga, T. M., Baker, F. L., Batatinha, H., Pedlar, C. R., Burgess, S. C., Gustafson, M. P., Katsanis, E., & Simpson, R. J. (2024). COVID-19 vaccination produces exercise-responsive SARS-CoV-2-specific T-cells regardless of infection history. Journal of sport and health science.
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  The mobilization and redistribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T-cells and neutralizing antibodies (nAbs) during exercise is purported to increase immune surveillance and protect against severe coronavirus disease 2019 (COVID-19). We sought to determine if COVID-19 vaccination would elicit exercise-responsive SARS-CoV-2 T-cells and transiently alter nAb titers.
• Simpson, R., Katsanis, E., Burgess, S. C., Seckeler, M., Kulangara, T., Batatinha, H., Smith, K. A., Zuniga, T. M., & Baker, F. L. (2023). Exercise mobilizes diverse antigen specific T-cells and elevates neutralizing antibodies in humans with natural immunity to SARS CoV-2. Brain, Behavior, and Immunity – Health.
• Simpson, R., Katsanis, E., Gustafson, M. P., Lau, B., Baker, F. L., & Zuniga, T. M. (2023). Clonal kinetics and single-cell transcriptional profiles of T-cells mobilized to blood by acute exercise. Medicine & Science in Sports & Exercise.
• Baker, F. L., Mylabathula, P. L., Diak, D. M., Niemiro, G. M., Markofski, M. M., Crucian, B. E., Katsanis, E., & Simpson, R. J. (2022). IL-2 and zoledronic acid therapy restores the in vivo anti-leukemic activity of human lymphocytes pre-exposed to simulated microgravity. Frontiers in Biosciences - Landmark. doi:10.21203/rs.3.rs-1374348/v1
• Baker, F. L., Smith, K. A., Zúñiga, T. M., Batatinha, H., Pedlar, C. R., Burgess, S. C., Katsanis, E., & Simpson, R. J. (2022). Acute Exercise Mobilizes Functional SARS-CoV-2 Specific T-Cells And Elevates Neutralizing Antibodies In Previously Infected Individuals: 1265. Medicine & Science in Sports & Exercise, 54(9S), 312-313. doi:10.1249/01.mss.0000878948.45105.37
• Niemiro, G. M., Coletta, A. M., Agha, N. H., Mylabathula, P. L., Baker, F. L., Brewster, A. M., Bevers, T. B., Fuentes-Mattei, E., Basen-Engquist, K., Katsanis, E., Gilchrist, S. C., & Simpson, R. J. (2022). Correction: Salutary effects of moderate but not high intensity aerobic exercise training on the frequency of peripheral T-cells associated with immunosenescence in older women at high risk of breast cancer: a randomized controlled trial. Immunity & ageing : I & A, 19(1), 30.
• Zúñiga, T. M., Baker, F. L., Smith, K. A., Batatinha, H., Lau, B., Gustafson, M. P., Katsanis, E., & Simpson, R. J. (2022). Acute exercise mobilizes NKT-like cells with a cytotoxic transcriptomic profile but does not augment the potency of cytokine-induced killer (CIK) cells. Frontiers in immunology, 13, 938106.
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  CD3/CD56 Natural killer (NK) cell-like T-cells (NKT-like cells) represent
• Baker, F. L. (2021). Acute exercise increases immune responses to SARS CoV-2 in a previously infected man. Brain, Behavior, & Immunity - Health.
• Baker, F. L. (2021). Exercise to Support Optimal Immune Function. ACSM's Health and Fitness Journal.
• Baker, F. L. (2021). Human Lymphocytes Mobilized With Exercise Extend Survival And Lower Leukemic Burden In Xenogeneic Mice: 1134. Medicine & Science in Sports & Exercise, 53(8S), 367-367. doi:10.1249/01.mss.0000763528.05151.3e
• Baker, F. L. (2021). Mental health, physical symptoms and biomarkers of stress during prolonged exposure to Antarctica's extreme environment. Acta Astronautica.
• Baker, F. L. (2021). Regulatory Dendritic Cells Induced by Bendamustine Are Associated With Enhanced Flt3 Expression and Alloreactive T-Cell Death. Frontiers in Immunology.
• Baker, F. L. (2021). The effects of normoxic endurance exercise on erythropoietin (EPO) production and the impact of selective β1 and non-selective β1 + β2 adrenergic receptor blockade. European Journal of Applied Physiology.
• Baker, F. L. (2021). The impact of high-intensity interval exercise training on NK-cell function and circulating myokines for breast cancer prevention among women at high risk for breast cancer. Breast Cancer Research and Treatment.
• Baker, F. L. (2022). Recent COVID-19 vaccination has minimal effects on the physiological responses to graded exercise in physically active healthy people. Journal of Applied Physiology.
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  Athletes are advised to receive the COVID-19 vaccination to protect them from SARS CoV-2 infection during major competitions. Despite this, many athletes are reluctant to get the COVID-19 vaccine due to concerns that symptoms of vaccinosis may impair athletic performance. OBJECTIVE: To determine the effects of COVID-19 vaccination on the physiological responses to graded exercise. METHODS: Healthy physically active participants completed a 20-minute bout of graded cycling exercise at intensities corresponding to 50, 60, 70 and 80% of the pre-determined V̇O2max before and ~21 days after receiving the COVID-19 vaccine (2 dose Pfizer mRNA or 1 dose Johnson&Johnson). RESULTS: Vaccination had no effect on a large number of physiological responses to exercise measured in blood (e.g. lactate, epinephrine, cortisol) and by respiratory gas exchange (e.g. oxygen uptake, CO2 production, ventilation, respiratory exchange ratio, predicted V̇O2max, ventilatory threshold) (p>0.05). We did, however, find significant elevations in heart rate (~5 bpm) and norepinephrine (p = 0.006 and 0.04, respectively) in response to vigorous (e.g. 70-80% V̇O2max) intensity exercise after vaccination, particularly in those that received the two shot Pfizer mRNA vaccine regimen. These findings held true when compared to demographically matched controls who completed identical bouts of exercise several weeks apart without receiving a vaccine. CONCLUSION: Recent COVID-19 vaccination has minimal effects on the physiological responses to graded exercise in physically active healthy people. The small elevations in cardiovascular and neuroendocrine responses to exercise after the Pfizer mRNA vaccine regimen could have implications for athletes at the elite level and warrants investigation.
• Baker, F. L., Niemiro, G. M., Coletta, A. M., Agha, N. H., Mylabathula, P. L., Brewster, A. M., Bevers, T. B., Fuentes-Mattei, E., Basen-Engquist, K., Katsanis, E., Gilchrist, S. C., & Simpson, R. (2022). Salutary effects of moderate but not high intensity aerobic exercise training on the frequency of peripheral T-cells associated with immunosenescence in older women at high risk of breast cancer: a randomized controlled trial. Immunity & Ageing. doi:10.21203/rs.3.rs-845373/v1
• Agha, N. H., Baker, F. L., Kunz, H. E., Spielmann, G., Mylabathula, P. L., Rooney, B. V., Mehta, S. K., Pierson, D. L., Laughlin, M. S., Markofski, M. M., Crucian, B. E., & Simpson, R. J. (2020). Salivary antimicrobial proteins and stress biomarkers are elevated during a 6-month mission to the International Space Station. Journal of applied physiology (Bethesda, Md. : 1985), 128(2), 264-275.
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  As the international space community plans for manned missions to Mars, spaceflight-associated immune dysregulation has been identified as a potential risk to the health and safety of the flight crew. There is a need to determine whether salivary antimicrobial proteins, which act as a first line of innate immune defense against multiple pathogens, are altered in response to long-duration (>6 mo) missions. We collected 7 consecutive days of whole and sublingual saliva samples from eight International Space Station (ISS) crewmembers and seven ground-based control subjects at nine mission time points, ~180 and ~60 days before launch (L-180/L-60), on orbit at flight days ~10 and ~90 (FD10/FD90) and ~1 day before return (R-1), and at R+0, R+18, R+33, and R+66 days after returning to Earth. We found that salivary secretory (s)IgA, lysozyme, LL-37, and the cortisol-to-dehydroepiandrosterone ratio were elevated in the ISS crew before (L-180) and during (FD10/FD90) the mission. "Rookie" crewmembers embarking on their first spaceflight mission had lower levels of salivary sIgA but increased levels of α-amylase, lysozyme, and LL-37 during and after the mission compared with the "veteran" crew who had previously flown. Latent herpesvirus reactivation was distinct to the ~6-mo mission crewmembers who performed extravehicular activity ("spacewalks"). Crewmembers who shed at least one latent virus had higher cortisol levels than those who did not shed. We conclude that long-duration spaceflight alters the concentration and/or secretion of several antimicrobial proteins in saliva, some of which are related to crewmember flight experience, biomarkers of stress, and latent viral reactivation. Spaceflight-associated immune dysregulation may jeopardize future exploration-class missions. Salivary antimicrobial proteins act as a first line of innate immune defense. We report here that several of these proteins are elevated in astronauts during an International Space Station mission, particularly in those embarking on their first space voyage. Astronauts who shed a latent herpesvirus also had higher concentrations of salivary cortisol compared with those who did not shed. Stress-relieving countermeasures are needed to preserve immunity and prevent viral reactivation during prolonged voyages into deep space.
• Baker, F. L. (2020). The effects of β1 and β1+2 adrenergic receptor blockade on the exercise-induced mobilization and ex vivo expansion of virus-specific T cells: implications for cellular therapy and the anti-viral immune effects of exercise. Cell Stress and Chaperones.
• Baker, F. L. (2019). NK cell function is impaired during long-duration spaceflight. Journal of Applied Physiology.
• Baker, F. L., Bigley, A. B., Agha, N. H., Pedlar, C. R., O'Connor, D. P., Bond, R. A., Bollard, C. M., Katsanis, E., & Simpson, R. J. (2019). Systemic β-Adrenergic Receptor Activation Augments the Expansion and Anti-Tumor Activity of Vγ9Vδ2 T-Cells. Frontiers in immunology, 10, 3082.
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  TCR-gamma delta (γδ) T-cells are considered important players in the graft-vs.-tumor effect following allogeneic hematopoietic cell transplantation (alloHCT) and have emerged as candidates for adoptive transfer immunotherapy in the treatment of both solid and hematological tumors. Systemic β-adrenergic receptor (β-AR) activation has been shown to mobilize TCR-γδ T-cells to the blood, potentially serving as an adjuvant for alloHCT and TCR-γδ T-cell therapy. We investigated if systemic β-AR activation, using acute dynamic exercise as an experimental model, can increase the mobilization, expansion, and anti-tumor activity of TCR-γδ T-cells isolated from the blood of healthy humans. We also sought to investigate the β-AR subtypes involved, by administering a preferential β-AR antagonist (bisoprolol) and a non-preferential β + β-AR antagonist (nadolol) prior to exercise as part of a randomized placebo controlled cross-over experiment. We found that exercise mobilized TCR-γδ cells to blood and augmented their expansion by ~182% compared to resting blood when stimulated with IL-2 and ZOL for 14-days. Exercise also increased the proportion of CD56+, NKG2D+/CD62L-, CD158a/b/e+ and NKG2A- cells among the expanded TCR-γδ cells, and increased their cytotoxic activity against several tumor target cells (K562, U266, 221.AEH) by 40-60%. Blocking NKG2D on TCR-γδ cells eliminated the augmented cytotoxic effects of exercise against U266 target cells. Furthermore, administering a β + β-AR (nadolol), but not a β-AR (bisoprolol) antagonist prior to exercise abrogated the exercise-induced enhancement in TCR-γδ T-cell mobilization and expansion. Furthermore, nadolol completely abrogated while bisoprolol partially inhibited the exercise-induced increase in the cytotoxic activity of the expanded TCR-γδ T-cells. We conclude that acute systemic β-AR activation in healthy donors markedly augments the mobilization, expansion, and anti-tumor activity of TCR-γδ T-cells and that some of these effects are due to β-AR signaling and phenotypic shifts that promote a dominant activating signal via NKG2D. These findings highlight β-ARs as potential targets to favorably alter the composition of allogeneic peripheral blood stem cell grafts and improve the potency of TCR-γδ T-cell immune cell therapeutics.
• Baker, F. L. (2018). Cytomegalovirus: an unlikely ally in the fight against blood cancers?. Clinical and Experimental Immunology.
• Baker, F. L. (2018). Relationships between cardiorespiratory fitness and markers of senescence and exhaustion in peripheral blood CD8+ T-cells and NK-cells. Annals of Research in Sport and Physical Activity.
• Baker, F. L. (2018). Vigorous exercise mobilizes CD34+ hematopoietic stem cells to peripheral blood via the β 2 -adrenergic receptor. Brain, Behavior, and Immunity.
• Baker, F. L. (2018). β2-Adrenergic receptor signaling mediates the preferential mobilization of differentiated subsets of CD8+ T-cells, NK-cells and non-classical monocytes in response to acute exercise in humans. Brain, Behavior, and Immunity.

Presentations

• Leite, G., Smith, K. A., Zuniga, T. M., Batatinha, H., Simpson, R. J., Katsanis, E., & Baker, F. L. (2024, September).

  Exercise mobilizes multi-potent viral-specific T-cells enhancing the IFN-gamma response after viral peptide stimulation in healthy humans 

  . International Society of Exercise Immunology Meeting 2024.
• Baker, F. L. (2024).

  Exercise Immuno-Oncology: From the Tumor Microenvironment to Clinical Trials” 

  . American College of Sports Medicine Annual Meeting 2024.
• Baker, F. L. (2024, April).

  Exercise and HDAC Inhibitors as Adjuvants for Allogeneic γδ T-Cell Therapies” 

  . MD Anderson Department of Pediatrics Grand Rounds.
• McKenzie, G., Katsanis, E., Simpson, R. J., & Baker, F. L. (2024, September).

  Daratumumab Augments Exercise Expanded γδ T-cells Cytotoxic Function against Multiple Myeloma 

  . International Society of Exercise Immunology Meeting 2024.

Poster Presentations

• Baker, F. L. (2024, June). Evidence of Oxidative Stress and Persistent Inflammation in American Style-Football Players. American College of Sports Medicine Annual Meeting 2024.
• Baker, F. L., Garland, L. L., Curran, F., Ducey, I., Gibbons, O., Torres, E., Paine-Murrieta, G., & Chilton, F. S. (2024, November). Targeting T-Cell Migration Inhibition via Blocking Group X Secreted Phospholipase A2 (PLA2-X) Activity: A Novel Strategy to Overcome Immunotherapy Resistance in Non-Small Cell Lung Cancers.. University of Arizona Cancer Center Scientific Retreat Poster Presentation. UACC Cancer Center: UACC.
• Batatinha, H., Niemiro, G. M., Pena, N., Hoskin, G., Mylabathula, P., Baker, F. L., Zuniga, T., Smith, K. A., Diak, D., Seckeler, M., Simpson, R., & Katsanis, E. (2024, April). Acute systemic beta-adrenergic receptor activation to improve graft composition and outcomes in hematopoietic stem cell transplantation. American Association for Cancer Research Annual Meeting 2024. San Diego.