Expansion of tumor-reactive CD8+ T cell clonotypes occurs in the spleen in response to immune checkpoint blockade
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nihms-2033197.pdf
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Accepted version
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Author(s)
Morgan, Duncan M
Horton, Brendan L
Bhandarkar, Vidit
Van, Richard
Dinter, Teresa
Zagorulya, Maria
Love, J Christopher
Spranger, Stefani
Date Issued
September 13, 2024
Journal
Science Immunology
Publisher
American Association for the Advancement of Science
Citation
Duncan M. Morgan et al. ,Expansion of tumor-reactive CD8+ T cell clonotypes occurs in the spleen in response to immune checkpoint blockade.Sci. Immunol. 9, eadi3487 (2024).
Version
Author's final manuscript
Abstract
Immune checkpoint blockade (ICB) enhances T cell responses against cancer, leading to long-term
survival in a fraction of patients. CD8+ T cell differentiation in response to chronic antigen
stimulation is highly complex and it remains unclear precisely which T cell differentiation states at
which anatomic sites are critical for the response to ICB. We identified an intermediate-exhausted
population in the white pulp of the spleen which underwent significant expansion in response
to ICB and gave rise to the majority of tumor-infiltrating clonotypes. Increased systemic antigen
perturbed differentiation of this population towards a most circulatory exhausted_KLR state, while
a lack of cross-presented tumor-antigen blunted its differentiation in the spleen. An analogous
population of exhausted_KLR CD8+ T cells in human blood samples exhibited diminished tumortrafficking ability. Collectively, our data demonstrate the critical role of antigen density within the
spleen for the differentiation and expansion of T cell clonotypes in response to ICB.
MIT Department
Massachusetts Institute of Technology. Department of Chemical Engineering
Koch Institute for Integrative Cancer Research at MIT
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1126/sciimmunol.adi3487
