About

Stephen Hedrick is an Emeritus Professor of Molecular Biology at UCSD. His research activities and funding focus on immunology, particularly T cell biology, immune regulation, and vaccine strategies. He has contributed to understanding the molecular basis of T cell memory, lymphocyte homeostasis, and immune responses to chronic infections and neoplasia. Hedrick has been recognized for his scientific contributions with awards such as election to the National Academy of Sciences in 2024 and being named a Stephen M Hedrick Distinguished Fellow of the American Association of Immunologists in 2019. His work involves elucidating the roles of transcription factors like Foxo and Foxo1 in immune cell function, as well as exploring immune checkpoint pathways and gene regulation in immune responses.

Research topics

• Biology
• Genetics
• Cell biology
• Medicine
• Neuroscience

Selected publications

• BPS2025 - Differential biophysical and functional properties of human vs. mouse PD1

  Biophysical Journal · 2025-02-01

  article
  PublisherDOI

• A Multicenter, Blinded, Intensity Modulated Proton Therapy Competitive Planning Study for Head and Neck Cancers: The Urgency for Guidelines and Standards

  International Journal of Radiation Oncology*Biology*Physics · 2025-09-01

  article
  PublisherDOI

• Functional differences between rodent and human PD-1 linked to evolutionary divergence

  Science Immunology · 2025-01-03 · 29 citations

  articleOpen access

  Mechanistic understanding of the inhibitory immunoreceptor PD-1 is largely based on mouse models, but human and mouse PD-1 share only 59.6% amino acid identity. Here, we found that human PD-1 is more inhibitory than mouse PD-1, owing to stronger interactions with the ligands PD-L1 and PD-L2 and more efficient recruitment of the effector phosphatase Shp2. In a mouse melanoma model with adoptively transferred T cells, humanization of a PD-1 intracellular domain disrupted the antitumor activity of CD8 + T cells and increased the magnitude of anti–PD-1 response. We identified a motif highly conserved across vertebrate PD-1 orthologs, absent in rodents, as a key determinant for differential Shp2 recruitment. Evolutionary analysis suggested that PD-1 underwent a rodent lineage–specific functional attenuation during evolution. Together, our study uncovers species-specific features of the PD-1 pathway, with implications for PD-1 evolution and differential anti–PD-(L)1 responses in mouse models and human patients.

  PublisherOA PDFDOI

• Human PD1 verus mouse PD1 - how different are they? 3290

  The Journal of Immunology · 2025-11-01

  articleOpen access

  Abstract Description Mechanistic understanding of the inhibitory immunoreceptor PD1 is largely based on mouse models, but human and mouse PD1 orthologs exhibit only 59.6% identity in amino acid sequences. We show that human PD1 is more inhibitory than mouse PD1 due to stronger interactions with the ligands PDL1 and PDL2 and with the effector phosphatase Shp2. A novel motif highly conserved among PD1 orthologs in vertebrates except in rodents is primarily responsible for the differential Shp2 recruitment. Evolutionary analysis suggested that rodent PD1 orthologs uniquely underwent functional relaxation, particularly during the K-Pg boundary. Humanization of the PD1 intracellular domain disrupted the anti-tumor activity of mouse T cells while increasing the magnitude of anti-PD1 response. Together, our study uncovers species-specific features of the PD1 pathway, with implications to PD1 evolution and differential anti-PD(L)1 responses in mouse models and human patients. Funding Sources Supported by R37 CA239072 from the National Institute of Health, the Hartwell Foundation, Human Frontiers Science Program and JST PRESTO grant (JPMJPR22EB) Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

  PublisherOA PDFDOI

• Multiple institutional planning and dosimetry comparisons for proton pencil beam scanning

  International Journal of Particle Therapy · 2024-03-01

  articleOpen access
  PublisherDOI

• Enhancing intermediate dose falloff in fractionated stereotactic radiosurgery for brain metastases: Combining apertures with pencil beam scanning

  International Journal of Particle Therapy · 2024-03-01

  articleOpen access
  PublisherDOI

• Reducing radiation dermatitis severity in breast cancer patients using a spot-delete technique in pencil beam scanning proton therapy

  International Journal of Particle Therapy · 2024-03-01

  articleOpen access1st authorCorresponding
  PublisherDOI

• Impact of spot placement on linear energy transfer in pencil beam scanning proton therapy for breast cancer treatment

  International Journal of Particle Therapy · 2024-03-01

  articleOpen access1st authorCorresponding
  PublisherDOI

• Evaluation of cloud based independent Monte Carlo calculation for pencil beam scanning proton therapy quality assurance

  International Journal of Particle Therapy · 2024-03-01

  articleOpen access
  PublisherDOI

• Evolutionary fingerprint in rodent PD1 confers weakened activity and enhanced tumor immunity compared to human PD1

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-09-24

  preprintOpen access

  Mechanistic understanding of the immune checkpoint receptor PD1 is largely based on mouse models, but human and mouse PD1 orthologs exhibit only 59.6% identity in amino acid sequences. Here we show that human PD1 is more inhibitory than mouse PD1 due to stronger interactions with the ligands PDL1 and PDL2 and with the effector phosphatase Shp2. A novel motif highly conserved among PD1 orthologs in vertebrates except in rodents is primarily responsible for the differential Shp2 recruitment. Evolutionary analysis suggested that rodent PD1 orthologs uniquely underwent functional relaxation, particularly during the K-Pg boundary. Humanization of the PD1 intracellular domain disrupted the anti-tumor activity of mouse T cells while increasing the magnitude of anti-PD1 response. Together, our study uncovers species-specific features of the PD1 pathway, with implications to PD1 evolution and differential anti-PD(L)1 responses in mouse models and human patients.

  PublisherOA PDFDOI

Recent grants

• NIH Grant R37AI021372

  NIH · $3.7M · 2007

• NIH Grant R01CA076554

  NIH · $660k · 2001

• NIH Grant R01AI021372

  NIH · $4.9M · 2012

• Mutagenic chain reaction-facilitated immunotherapy

  NIH · $3.3M · 2016–2021

• NIH Grant R01GM035880

  NIH · $2.0M · 1997

Frequent coauthors

• Mark M. Davis

  Howard Hughes Medical Institute

  53 shared

• Carol D. Katayama

  University of California, San Diego

  28 shared

• David I. Cohen

  Stanford University

  27 shared

• Thandi M. Onami

  National Institute of Allergy and Infectious Diseases

  22 shared

• Louis A. Matis

  22 shared

• Peter D’Eustachio

  NYU Langone Health

  22 shared

• Tatsuro Irimura

  Juntendo University

  21 shared

• Dawne M. Page

  Point Loma Nazarene University

  20 shared

Labs

• UCSD Molecular BiologyPI

Education

• Ph.D., Molecular Biology

  University of California, San Diego

  1983

• B.S., Biology

  University of California, San Diego

  1977

Awards & honors

• National Academy of Sciences 2024
• Stephen M Hedrick Distinguished Fellow, American Association…