Stephen Hatfield

Specializations

Immune-oncology
Cancer Immunotherapy
Immunology
Cancer Biology
Immunopharmacology

Overview

Dr. Hatfield’s laboratory focuses on the role of hypoxia and immunosuppressive A2A adenosine receptor (A2AR) signaling in cancer and infectious disease. Through pharmacological and gene-targeting approaches, these studies aim to further our understanding of the tumor-protecting mechanisms that lead to immune evasion. This has led to the current understanding that tumor hypoxia and subsequent accumulation of extracellular adenosine represent a major biochemical barrier (hypoxia-adenosinergic suppression) that prevents immune-mediated tumor elimination. Dr. Hatfield’s studies have implicated the blockade of A2AR as a feasible and translatable approach to improve cancer immunotherapies, including immune checkpoint inhibitors and CAR-T cell therapy. This is supported by promising results from recent clinical studies using A2AR antagonists for treatment of several forms of cancers. More recently, his lab has developed a multifaceted approach to genetically engineer ‘off the shelf’ CAR-T cells resistant to both biochemical and immunological inhibitory barriers. Using novel engineering strategies, his lab has generated CAR-T cells resistant to a diverse TME, unlocking the therapeutic potential of CAR-T cells against solid tumors.  Dr. Hatfield’s research also demonstrated the immune-enhancing effects of tumor oxygenation. These studies uncovered the molecular mechanisms of the therapeutic reversal of tumor hypoxia. Oxygenation reprograms the TME and improves anti-tumor responses, justifying the use of supplemental oxygen and oxygenation agents as immunological co-adjuvants to combine with cancer immunotherapies. The impact of these studies was reflected by subsequent editorials and commentaries in peer reviewed journals (e.g. Cancer Cell, Nature Reviews Cancer) and press releases in major media outlets. More recently, his lab has focused on the next stage of this research by repurposing oxygenation agents (e.g. perfluorocarbon nano-emulsions) and blood substitutes for cancer immunotherapy. Dr. Hatfield’s research has demonstrated that combination of oxygen carrying nanoemulsions and respiratory hyperoxia synergize to alleviate tumor hypoxia-induced suppression and promote anti-tumor immune responses.

Courses Taught

Awards

2022 – Gerald E. Schumacher Faculty Research Award
2022 – Tufts Clinical and Translational Science Institute (CTSI) Award
2021 – Tier-1 Award, Northeastern University
2020 – COVID-19 Research Award, Northeastern University
2015 – NEIC Young Investigator Award

Grants

Title: Overcoming vaccine-associated hypoxia with advanced biomaterials to enhance cancer immunotherapy
Sponsor: NIH R01
07/01/2021 – 03/31/25
Role: PI

Title: Design and characterization of CART cells genetically-resitant to hypoxia-adenosinergic immunosuppression.
Sponsor: Beam Therapeutics (Sponsored Research Agreement)
02/01/2021 – 01//31/2024
Role: PI

Title: Investigations of the anti-tumor effects of a dual A2AR/A2BR antagonist.
Sponsor: Bugworks, LLC (Sponsored Research Agreement)
09/01/2022 – 08/29/2024
Role: PI

Patents

Issued USA Patent: Method for generation of broadly neutralizing anti-pathogen antibodies.
Inventors: Michail Sitkovsky, Robert Abbot, Stephen Hatfield

Issued USA Patent: Methof for generation of oxygen-generating cryogels.
Inventors: Sidi Bencherif, Thibualt Colombani, Michail Sitkovsky, Adnan Memic, Stephen Hatfield

Pending USA Patent: Modified Immune cells and methods.
Inventors: Ryan Murray, Michail Sitkovsky, Stephen Hatfield, Beam Therapeuticts

Publications

Murray R, Navarrete N, Desai K, Chowdhury R, Chilakapati S, Chong B, Messane A, Sobon H, Rocha J., Musenge F, Camblin A, Ciaramella G, Sikovsky M, Maldini C, Hatfield SM. Comprehensive genome editing confers ‘off-the-shelf’ CAR-T cells superior efficacy against solid tumors. BioRxiv [Preprint]. August 4, 2023. doi: https://doi.org/10.1101/2023.08.03.551705. Under Review at Nature Comm., Jan. 2024

Halpin-Veszeleiova K, Mallouh M, Apro A, Romero N, Bahr C, Shin M, Ward K, Rosenberg L, Sitkovsky M, Spiess B, Hatfield SM. Oxygen carrying nanoemulsions and respiratory hyperoxia eliminate tumor hypoxia-induced suppression and improve cancer immunotherapy. BioRxiv [Preprint]. Feb doi: https://doi.org/10.1101/2024.02.17.580835. Under Review at J Clin Invest: Insight, Oct. 2023

Halpin-Veszeleiova K, Hatfield SM. Therapeutic Targeting of Hypoxia-A2-Adenosinergic Pathway in COVID-19 Patients. Physiology, 2022 Jan 1;37(1):46-52. doi: 10.1152/physiol.00010.2021.

Hatfield S, Sitkovsky M. Antihypoxic oxygenation agents with respiratory hyperoxia to improve cancer immunotherapy. J Clin Invest, 2020 Sep 28;137554. doi: 10.1172/JCI137554.

Steingold J, Hatfield SM. Targeting hypoxia-A2A adenosinergic immunosuppression of antitumor T cells during cancer immunotherapy. Frontiers Immunology. 2020 Sep 29, doi: 10.3389/fimmu.2020.570041

Veszeleiova K, Hatfield S. Oxygenation and A2AR blockade to eliminate hypoxia/HIF-1α-adenosinergic immunosuppressive axis and improve cancer immunotherapy. Curr Opin Pharmacol. 2020 22;53:84-90. doi: 10.1016/j.coph.2020.07.005.

Sorrentino C, Hossain F, Rodriguez P, Sierra RA, Pannuti A, Hatfield S, Osborne BA, Minter LM, Miele L, Morello S. Adenosine A2A Receptor Stimulation Inhibits TCR-Induced Notch1 Activation in CD8+T-Cells. Frontiers Immunology. 2019 May 3;10:935. doi: 10.3389/fimmu.2019.00935.

Kjaergaard J*, Hatfield SM*, Jones G, Ohta A and Sitkovsky M. A2A adenosine receptor gene-deletion or synthetic A2A antagonist liberate tumor-reactive CD8+ T-cells from tumor-induced immunosuppression. J Immunol. 2018 Jul 15;201(2):782-791. doi: 10.4049/jimmunol.1700850.

Hatfield SM, Kjaergaard J, Lukashev D, Schreiber TH, Belikoff B, Abbott R, Sethumadhavan S, Philbrook P, Ko K, Cannici R, Rodig S, Kutok JL, Karger B, Podack ER, Ohta A, Sitkovsky M. Immunological mechanisms of the anti-tumor effects of supplemental oxygenation. Science Translational Medicine, 2015 Mar 4;7(277):277ra30. doi: 10.1126/scitranslmed.aaa1260.

Hatfield SM, Kjaergaard J, Lukashev D, Belikoff B, Schreiber TH, Sethumadhavan S, Abbott R, Philbrook P, Thayer M, Shujia D, Rodig S, Kutok JL, Ren J, Ohta A, Podack ER, Karger B, Jackson EK, Sitkovsky M. Systemic oxygenation weakens the hypoxia and hypoxia inducible factor 1α-dependent and extracellular adenosine- mediated tumor protection. J Mol Med; 2014 Aug 15. PMID: 25120128

Stephen Hatfield

PhD

Education & Degrees