Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1-CD8+ Tumor-Infiltrating T Cells
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An improved understanding of the anti-tumor CD8+ T cell response after checkpoint blockade would enable more informed and effective therapeutic strategies. Here we examined the dynamics of the effector response of CD8+ tumor-infiltrating lymphocytes (TILs) after checkpoint blockade therapy. Bulk and single-cell RNA profiles of CD8+ TILs after combined Tim-3+PD-1 blockade in preclinical models revealed significant changes in the transcriptional profile of PD-1- TILs. These cells could be divided into subsets bearing characterstics of naive-, effector-, and memory-precursor-like cells. Effector- and memory-precursor-like TILs contained tumor-antigen-specific cells, exhibited proliferative and effector capacity, and expanded in response to different checkpoint blockade therapies across different tumor models. The memory-precursor-like subset shared features with CD8+ T cells associated with response to checkpoint blockade in patients and was compromised in the absence of Tcf7. Expression of Tcf7/Tcf1 was requisite for the efficacy of diverse immunotherapies, highlighting the importance of this transcriptional regulator in the development of effective CD8+ T cell responses upon immunotherapy.
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Terminal Tex (Ttex) cells accumulate over time and respond poorly to immune checkpoint blockade therapies.
“Conversely, terminal Tex (Ttex) cells accumulate over time and respond poorly to ICB therapies8,11–13.”
From Proteotoxic stress response drives T cell exhaustion and immune evasion (2025) · cites this paper as [12]
The Discussion (page unavailable) says chronically stimulated PD-1+ CD8+ T cells can develop a fixed epigenetic profile that limits reprogramming by checkpoint blockade, supporting the poor-response portion. Neither that passage nor the relevant Results passages establish that terminally exhausted cells accumulate over time; the paper also does not equate all PD-1+ cells with terminal exhaustion. (LLM, conf=0.82)
Experimental — accuracy not yet measuredIn mouse chronic viral infection and syngeneic tumor models, TCF7+ cells have greater proliferative potential and less differentiated phenotypes during immunotherapy.
“Consistent with this model, in mouse chronic viral infection and syngeneic tumor models, TCF7+ cells have increased proliferative potential and less differentiated phenotypes during immunotherapies (Kurtulus et al., 2019; Siddiqui et al., 2019; Wu et al., 2016)”
From Pooled Knockin Targeting for Genome Engineering of Cellular Immunotherapies (2020) · cites this paper as Kurtulus et al., 2019
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Clonal replacement of tumor-specific T cells following PD-1 blockade
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T cell stemness and dysfunction in tumors are triggered by a common mechanism
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Huang, Q., Wu, X., Wang, Z., Chen, X., Wang, L., Lu, Y., Xiong, D., Liu, Q., Tian, Y., Lin, H., et al. (2022) · Cell · doi:10.1016/j.cell.2022.09.020 · Cited by 486 · see citing works
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Li, W., Lu, L., Lu, J., Wang, X., Yang, C., Jin, J., Wu, L., Hong, X., Li, F., Cao, D., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.aay9013 · Cited by 305 · see citing works
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Proteotoxic stress response drives T cell exhaustion and immune evasion
Wang, Y., Ma, A., Song, N.-J., Shannon, A. E., Amankwah, Y. S., Chen, X., Wu, W., Wang, Z., Saadey, A. A., Yousif, A., et al. (2025) · Nature · doi:10.1038/s41586-025-09539-1 · Cited by 68 · see citing works
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- Authors
- Kurtulus, S., Madi, A., Escobar, G., Klapholz, M., Nyman, J., Christian, E., Pawlak, M., Dionne, D., Xia, J., Rozenblatt-Rosen, O., Kuchroo, V. K., Regev, A., & Anderson, A. C.
- Affiliations
- Brigham and Women's Hospital (US)
- Broad Institute (US)
- Corresponding author
- Kuchroo, Vijay K.
- Regev, Aviv
- Anderson, Ana C.
- ORCID
- Venue
- Immunity
- Publisher
- Elsevier BV
- Published
- 2019-01
- Volume
- 50
- Issue
- 1
- Pages
- 181-194.e6
- ISSN
- 1074-7613 (ISSN-L)
- PMC
- PMC6336113
- OpenAlex
- W2908581980
- Cited by
- 636
- References
- 80
- Citations by year
- 2026: 52 · 2025: 73 · 2024: 97 · 2023: 80 · 2022: 96 · 2021: 106 · 2020: 88 · 2019: 44
- FWCI
- 34.90
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Immunity (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (R01NS045937, P01AI073748, R01CA187975)
- American Cancer Society (RSG-11-057-01-LIB)
- Klarman Cell Observatory at the Broad Institute and HHMI
- EMBO
- 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
- immune checkpoint blockade, PD-1, TIM-3, CD8+ T cells, tumor-infiltrating lymphocytes, T cell differentiation, effector T cells, TCF1, single-cell RNA sequencing, antitumor immunity, tumor antigen-specific T cells
- MeSH terms
- Hepatitis A Virus Cellular Receptor 2, Animals, Antibodies, Monoclonal, Antigens, Neoplasm, Humans, Immunologic Memory, Immunotherapy, Melanoma, Experimental, Mice, Inbred C57BL, Neoplasms, Experimental, T-Lymphocyte Subsets, Lymphocytes, Tumor-Infiltrating, CD8-Positive T-Lymphocytes, Cell Proliferation, Mice, Hepatocyte Nuclear Factor 1-alpha, Transcriptome, Programmed Cell Death 1 Receptor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
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