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PD-1 blockade-unresponsive human tumor-infiltrating CD8⁺ T cells are marked by loss of CD28 expression and rescued by IL-15.

ABSTRACT: Blockade of programmed death-1 (PD-1) reinvigorates exhausted CD8⁺ T cells, resulting in tumor regression in cancer patients. Recently, reinvigoration of exhausted CD8⁺ T cells following PD-1 blockade was shown to be CD28-dependent in mouse models. Herein, we examined the role of CD28 in anti-PD-1 antibody-induced human T cell reinvigoration using tumor-infiltrating CD8⁺ T cells (CD8⁺ TILs) obtained from non-small-cell lung cancer patients. Single-cell analysis demonstrated a distinct expression pattern of CD28 between mouse and human CD8⁺ TILs. Furthermore, we found that human CD28⁺CD8⁺ but not CD28^-CD8⁺ TILs responded to PD-1 blockade irrespective of B7/CD28 blockade, indicating that CD28 costimulation in human CD8⁺ TILs is dispensable for PD-1 blockade-induced reinvigoration and that loss of CD28 expression serves as a marker of anti-PD-1 antibody-unresponsive CD8⁺ TILs. Transcriptionally and phenotypically, PD-1 blockade-unresponsive human CD28^-PD-1⁺CD8⁺ TILs exhibited characteristics of terminally exhausted CD8⁺ T cells with low TCF1 expression. Notably, CD28^-PD-1⁺CD8⁺ TILs had preserved machinery to respond to IL-15, and IL-15 treatment enhanced the proliferation of CD28^-PD-1⁺CD8⁺ TILs as well as CD28⁺PD-1⁺CD8⁺ TILs. Taken together, these results show that loss of CD28 expression is a marker of PD-1 blockade-unresponsive human CD8⁺ TILs with a TCF1^- signature and provide mechanistic insights into combining IL-15 with anti-PD-1 antibodies.

SUBMITTER: Kim KH

PROVIDER: S-EPMC8027446 | biostudies-literature |

REPOSITORIES: biostudies-literature

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PD-1 blockade-unresponsive human tumor-infiltrating CD8+ T cells are marked by loss of CD28 expression and rescued by IL-15

Project description:Blockade of programmed death-1 (PD-1) reinvigorates exhausted CD8+ T cells, resulting in tumor regression in cancer patients. Recently, reinvigoration of exhausted CD8+ T cells following PD-1 blockade was shown to be CD28-dependent in mouse models. Herein, we examined the role of CD28 in anti-PD-1-induced human T-cell reinvigoration using tumor-infiltrating CD8+ T cells (CD8+ TILs) obtained from non-small cell lung cancer patients. Single cell analysis demonstrated a distinct expression pattern of CD28 between mouse and human CD8+ TILs. Furthermore, we found that human CD28+CD8+, but not CD28–CD8+ TILs, responded to PD-1 blockade irrespective of B7/CD28 blockade, indicating that CD28 co-stimulation in human CD8+ TILs is dispensable for PD-1 blockade-induced reinvigoration, and loss of CD28 expression rather serve as a marker of anti-PD-1-unresponsive CD8+ TILs. Transcriptionally and phenotypically, PD-1 blockade-unresponsive human CD28–PD-1+CD8+ TILs exhibited characteristics of terminally exhausted CD8+ T cells with low TCF1 expression. Notably, CD28–PD-1+CD8+ TILs had preserved machinery to respond to IL-15, and IL-15 treatment enhanced proliferation of CD28–PD-1+CD8+ TILs as well as CD28+PD-1+CD8+ TILs. Taken together, we demonstrate loss of CD28 expression as a marker of PD-1 blockade-unresponsive human CD8+ TILs with TCF1– signature and provide mechanistic insights into combining IL-15 with anti-PD-1.

2020-05-01 | GSE145896 | GEO

PD-1 blockade-unresponsive human tumor-infiltrating CD8+ T cells are marked by loss of CD28 expression and rescued by IL-15

Project description:PD-1 blockade-unresponsive human tumor-infiltrating CD8+ T cells are marked by loss of CD28 expression and rescued by IL-15

| PRJNA608687 | ENA

Checkpoint Blockade Immunotherapy Induces Dynamic Changes in PD-1-CD8+ Tumor-Infiltrating T Cells.

Project description: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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Fewer tumour-specific PD-1+CD8+ TILs in high-risk "Infiltrating" HPV- HNSCC.

Project description:BackgroundThe prognosis of HPV- HNSCC was worse than that of HPV+ HNSCC. Analysis of tumours and tumour-infiltrating lymphocytes (TILs) may provide insight into the progression of HPV- HNSCC.MethodsThe tumour and TIL phenotypic characteristics of 134 HNSCC specimens (HPV- tumours were classified into "Infiltrating" and "Pushing" subtypes based on their different tumour nest configuration and prognosis) were retrospectively analysed. HNSCC data from the Cancer Genome Atlas (n = 263) were analysed for CD8α, HPV and overall survival (OS). A murine HNSCC model was used to verify the antitumour role of PD-1+CD8+ TILs.ResultsThe "Infiltrating" HPV- subtype showed shorter OS than the "Pushing" subtype. Moreover, there is a tendency from "Pushing" to "Infiltrating" subtype from the primary to the recurrent lesion. Different from total CD8+ TILs, tumour-specific PD-1+CD8+ TILs were fewer in invasive margin (IM) of "Infiltrating" HPV- tumours. PD-1+CD8+ TILs recognised autologous HNSCC cells and showed stronger inhibition of tumour growth in a murine HNSCC model resistant to PD-1 blockade.ConclusionsCoevolution of HPV- HNSCC and TILs is characterised by an "Infiltrating" phenotype and less tumour-specific PD-1+CD8+ TILs, which may provide a framework for further translational studies and patient stratification.

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CTLA-4 blockade boosts the expansion of tumor-reactive CD8+ tumor-infiltrating lymphocytes in ovarian cancer.

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PD-L1, Galectin-9 and CD8+ tumor-infiltrating lymphocytes are associated with survival in hepatocellular carcinoma.

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PD-1 blockade potentiates neoadjuvant chemotherapy in NSCLC via increasing CD127+ and KLRG1+ CD8 T cells.

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Combined immune checkpoint blockade increases CD8+CD28+PD-1+ effector T cells and provides a therapeutic strategy for patients with neuroblastoma.

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