Rescue of exhausted CD8 T cells by PD-1–targeted therapies is CD28-dependent
Open accessAbstract
Programmed cell death-1 (PD-1)-targeted therapies enhance T cell responses and show efficacy in multiple cancers, but the role of costimulatory molecules in this T cell rescue remains elusive. Here, we demonstrate that the CD28/B7 costimulatory pathway is essential for effective PD-1 therapy during chronic viral infection. Conditional gene deletion showed a cell-intrinsic requirement of CD28 for CD8 T cell proliferation after PD-1 blockade. B7-costimulation was also necessary for effective PD-1 therapy in tumor-bearing mice. In addition, we found that CD8 T cells proliferating in blood after PD-1 therapy of lung cancer patients were predominantly CD28-positive. Taken together, these data demonstrate CD28-costimulation requirement for CD8 T cell rescue and suggest an important role for the CD28/B7 pathway in PD-1 therapy of cancer patients.
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The observation that coactivation molecules and Th2 are most predictive likely stems from the importance of coactivation molecules such as CD28 in cancer immunotherapy response.
“This observation likely stems from the importance of coactivation molecules, such as CD28, which is essential for T cell activation after interacting with antigen-presenting cells, in cancer immunotherapy response62.”
From Predicting the tumor microenvironment composition and immunotherapy response in non-small cell lung cancer from digital histopathology images (2024) · cites this paper as [62]
The passages on the CD28/B7 pathway report that CD28 costimulation is necessary for effective PD-1 therapy in a murine tumor model and suggest a role in CD8 T-cell proliferation during PD-1 therapy in lung cancer patients. They do not establish that CD28 is universally essential for T-cell activation after interaction with antigen-presenting cells; the passage introducing CD28 says its signaling requirement varies with antigen exposure. (LLM, conf=0.83)
Experimental — accuracy not yet measuredCD28-expressing cells, rather than terminally differentiated effector cells, respond to PD-1 blockade with a proliferative burst and differentiation.
“Two recent studies have shown that it is indeed CD28-expressing cells rather than already terminally differentiated effector cells that respond to PD-1 blockade with a proliferative burst and differentiation (94, 95).”
From Anti-PD-1 and Anti-CTLA-4 Therapies in Cancer: Mechanisms of Action, Efficacy, and Limitations (2018) · cites this paper as [95]
The need for both T cell co-stimulation and IL-12 for maximal IFN-γ response likely reflects a requirement for CD28 to rescue exhausted CD8+ T cells and possibly PD-1 limiting CD28 co-stimulation.
“The requirement for both T cell co-stimulation and IL-12 to achieve maximal IFN-γ response likely reflected the need of CD28 to rescue exhausted CD8+ T cells, and possibly also the role of PD-1 in limiting CD28-mediated co-stimulation (Kamphorst et al., 2017; Hui et al., 2017).”
From Successful Anti-PD-1 Cancer Immunotherapy Requires T Cell-Dendritic Cell Crosstalk Involving the Cytokines IFN-γ and IL-12 (2018) · cites this paper as Kamphorst et al., 2017
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Self-citation
- Authors
- Kamphorst, A. O., Wieland, A., Nasti, T., Yang, S., Zhang, R., Barber, D. L., Konieczny, B. T., Daugherty, C. Z., Koenig, L., Yu, K., Sica, G. L., Sharpe, A. H., Freeman, G. J., Blazar, B. R., Turka, L. A., Owonikoko, T. K., Pillai, R. N., Ramalingam, S. S., Araki, K., & Ahmed, R.
- Affiliations
- Emory University (US)
- Central South University (CN)
- Harvard University (US)
- Brigham and Women's Hospital (US)
- Dana-Farber Cancer Institute (US)
- University of Minnesota (US)
- Corresponding author
- Ahmed, Rafi
- ORCID
- Venue
- Science
- Published
- 2017-03-31
- Volume
- 355
- Issue
- 6332
- Pages
- 1423-1427
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC5595217
- OpenAlex
- W2592666036
- Cited by
- 1,015
- References
- 25
- Citations by year
- 2026: 74 · 2025: 70 · 2024: 120 · 2023: 112 · 2022: 117 · 2021: 108 · 2020: 143 · 2019: 103 · 2018: 102 · 2017: 63 · 2016: 1 · 2015: 1
- FWCI
- 49.56
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (award296710, AI30048,AI080192,AI056299,AI054456,AI089955,CA72669,AI037691)
- Merck (award296711, 52507)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Keywords
- anti-PD-1 therapy, CD28 costimulation, exhausted CD8+ T cells, chronic viral infection, cancer immunotherapy, lung cancer, T cell proliferation, conditional gene deletion
- MeSH terms
- Animals, Carcinoma, Non-Small-Cell Lung, Humans, Immunotherapy, Lung Neoplasms, Lymphocytic Choriomeningitis, Gene Deletion, CD28 Antigens, B7-1 Antigen, CD8-Positive T-Lymphocytes, Mice, Metabolic Networks and Pathways, Programmed Cell Death 1 Receptor
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