PD-1 blockade and CDK4/6 inhibition augment nonoverlapping features of T cell activation in cancer

Ali, Lestat; Garrido-Castro, Ana C.; Lenehan, Patrick; Böllenrücher, Naïma; Stump, Courtney T.; Dougan, Michael; Goel, Shom; Shapiro, Geoffrey I.; Tolaney, Sara M.; Dougan, Stephanie K

doi:10.1084/jem.20220729

Cited by 9 publications

(6 citation statements)

References 52 publications

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“…Endogenous T-cell priming could be detected in our study, as pre-existing T-cell clones showed PD-1 blockade-induced expansion in the blood. This phenomenon was much more restrained than in similar analyses of paired peripheral blood samples in patients with metastatic breast cancer ( 10 ) or resectable HNSCC ( 18 ) treated with PD-1 blockade, although tumor sequencing was more extensive in the latter study, making it difficult to conclusively ascribe the observed differences to a defect in priming as opposed to better cross-matching of circulating T cells to their tumor-infiltrating counterparts. Collectively, these findings suggest that T-cell priming in PDAC does occur at a level consistent with other tumor types.…”

Section: Discussionmentioning

confidence: 89%

“…Single-cell RNA sequencing (scRNA-seq) was performed as previously described ( 10 ). Briefly, sorted single-cell suspensions prepared from each sample were washed twice with 0.05% UltraPure BSA (Invitrogen #AM2618) in PBS.…”

Section: Methodsmentioning

confidence: 99%

“…We therefore hypothesized that either tumor-specific T cells capable of reactivation with PD-1 blockade are not present in patients with pancreatic cancer, or that other factors impede successful antitumor immunity. To distinguish between these two possibilities and to determine whether PD-1 blockade had any measurable impact on T-cell responses in patients with pancreatic cancer, we evaluated peripheral blood and tumor samples from patients in the trial by single-cell transcriptional profiling and TCR clonotype tracking ( 10 ). These results suggest that PD-1–expressing exhausted T cells exist in patients with pancreatic cancer, and at least some of these are likely to be tumor-reactive.…”

Section: Introductionmentioning

confidence: 99%

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PD-1 Blockade Induces Reactivation of Nonproductive T-Cell Responses Characterized by NF-κB Signaling in Patients with Pancreatic Cancer

Ali,

Lenehan,

Cardot-Ruffino

et al. 2023

Clinical Cancer Research

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Purpose: Pancreatic ductal adenocarcinoma (PDAC) trials have evaluated CTLA-4 and/or PD-(L)1 blockade in patients with advanced disease where bulky tumor burden and limited time to develop anti-tumor T cells may have contributed to poor clinical efficacy. Here we evaluated peripheral blood and tumor T cells from patients with PDAC receiving neoadjuvant chemoradiation plus anti-PD-1 (pembrolizumab) versus chemoradiation alone. We analyzed whether PD-1 blockade successfully reactivated T cells in the blood and/or tumor to determine whether lack of clinical benefit could be explained by lack of reactivated T cells versus other factors. Experimental Design: We used single cell transcriptional profiling and TCR clonotype tracking to identify TCR clonotypes from blood that match clonotypes in the tumor. Results: PD-1 blockade increases the flux of TCR clonotypes entering cell cycle and induces an IFNγ signature like that seen in patients with other GI malignancies who respond to PD-1 blockade. However, these reactivated T cells have a robust signature of NF-κB signaling not seen in cases of PD-1 antibody response. Among paired samples between blood and tumor, several of the newly cycling clonotypes matched activated T cell clonotypes observed in the tumor. Conclusions: Cytotoxic T cells in the blood of PDAC patients remain sensitive to reinvigoration by PD-1 blockade and some have tumor-recognizing potential. Although these T cells proliferate and have a signature of IFN exposure, they also upregulate NF-κB signaling, which potentially counteracts the beneficial effects of anti-PD-1 reinvigoration and marks these T cells as non-productive contributors to anti-tumor immunity.

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Section: Discussionmentioning

confidence: 89%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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PD-1 Blockade Induces Reactivation of Nonproductive T-Cell Responses Characterized by NF-κB Signaling in Patients with Pancreatic Cancer

Ali,

Lenehan,

Cardot-Ruffino

et al. 2023

Clinical Cancer Research

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“…However, there is a very promising treatment for advanced breast tumors (hormone receptor-positive) with the drug CDK4/6, a cyclin-dependent kinase inhibitor that restores the immune response ( 58 , 59 ). Blocking PD-1 concomitantly with the administration of CDK4/6 has a synergistic protective effect against tumors by restoring T effector populations and promoting the formation of central memory T cells that preserve the immune-activating effect of α-CPI treatment ( 57 ). Studying the joint blockade of checkpoint molecules and drugs that stimulate central memory T cells in pulmonary PCM would be interesting.…”

Section: Discussionmentioning

confidence: 99%

Blocking the CTLA-4 and PD-1 pathways during pulmonary paracoccidioidomycosis improves immunity, reduces disease severity, and increases the survival of infected mice

Preite,

Borges,

Kaminski

et al. 2024

Front. Immunol.

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Immune checkpoint pathways, i.e., coinhibitory pathways expressed as feedback following immune activation, are crucial for controlling an excessive immune response. Cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed cell death protein-1 (PD-1) are the central classical checkpoint inhibitory (CPI) molecules used for the control of neoplasms and some infectious diseases, including some fungal infections. As the immunosuppression of severe paracoccidioidomycosis (PCM), a chronic granulomatous fungal disease, was shown to be associated with the expression of coinhibitory molecules, we hypothesized that the inhibition of CTLA-4 and PD-1 could have a beneficial effect on pulmonary PCM. To this end, C57BL/6 mice were infected with Paracoccidioides brasiliensis yeasts and treated with monoclonal antibodies (mAbs) α-CTLA-4, α-PD-1, control IgG, or PBS. We verified that blockade of CTLA-4 and PD-1 reduced the fungal load in the lungs and fungal dissemination to the liver and spleen and decreased the size of pulmonary lesions, resulting in increased survival of mice. Compared with PBS-treated infected mice, significantly increased levels of many pro- and anti-inflammatory cytokines were observed in the lungs of α-CTLA-4-treated mice, but a drastic reduction in the liver was observed following PD-1 blockade. In the lungs of α-CPI and IgG-treated mice, there were no changes in the frequency of inflammatory leukocytes, but a significant reduction in the total number of these cells was observed. Compared with PBS-treated controls, α-CPI- and IgG-treated mice exhibited reduced pulmonary infiltration of several myeloid cell subpopulations and decreased expression of costimulatory molecules. In addition, a decreased number of CD4+ and CD8+ T cells but sustained numbers of Th1, Th2, and Th17 T cells were detected. An expressive reduction in several Treg subpopulations and their maturation and suppressive molecules, in addition to reduced numbers of Treg, TCD4+, and TCD8+ cells expressing costimulatory and coinhibitory molecules of immunity, were also detected. The novel cellular and humoral profiles established in the lungs of α-CTLA-4 and α-PD-1-treated mice but not in control IgG-treated mice were more efficient at controlling fungal growth and dissemination without causing increased tissue pathology due to excessive inflammation. This is the first study demonstrating the efficacy of CPI blockade in the treatment of pulmonary PCM, and further studies combining the use of immunotherapy with antifungal drugs are encouraged.

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“…In particular, CD4 + T/CD8 + T was independent factor for disease-free survival of stage I–IIIA lung cancer ( 22 ). PD-1 and PD-L1 inhibitors block the binding of PD-L1 on the surface of tumor cells and PD-1 on the surface of activated lymphocytes, and enhance the killing effect of immune cells on tumor cells ( 23 , 24 ). However, not all patients with advanced NSCLC benefit from immunotherapy.…”

Section: Introductionmentioning

confidence: 99%

Changes in T lymphocyte subsets predict the efficacy of atezolizumab in advanced non-small cell lung cancer: a retrospective study

Wang,

Zhu,

Zhou

et al. 2023

J Thorac Dis

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Background It has remained unclear how programmed cell death ligand 1 (PD-L1) inhibitors affect peripheral blood lymphocyte (PBL) subsets in patients with advanced non-small cell lung cancer (NSCLC). This study assessed the predictive and prognostic value of PBL subsets in patients with advanced NSCLC who were treated with atezolizumab. Methods A total of 30 patients with advanced NSCLC treated with atezolizumab were selected as the observation group, and 30 healthy individuals were chosen as the control group during same period. Flow cytometry was used to detect lymphocyte subsets before and after treatment. The relationship between the changes of lymphocyte subsets and atezolizumab in the treatment of NSCLC was analyzed and calculated. Results Before treatment, compared with the control group, the number of CD3 + , CD4 + T, and CD4 + /CD8 + indexes in the observation group were significantly decreased, whereas the level of CD8 + was significantly increased. The number of CD3 + , CD4 + T, and CD4 + /CD8 + indexes gradually increased with the process of atezolizumab treatment, whereas the number of CD8 + T gradually decreased. After the 4 cycles, the number of CD3 + , CD4 + T, and CD4 + /CD8 + indexes were significantly increased, and the number of CD8 + was significantly decreased. In the observation group, 22 patients achieved partial response (PR)/stable disease (SD) and 8 patients achieved progressive disease (PD) after 4 cycles of atezolizumab treatment. Before treatment, there were no significant differences in the level of lymphocyte subsets between those who achieved PR/SD or PD. However, a significant difference in the level of lymphocyte subsets appeared after 4 cycles of atezolizumab treatment. Among the 22 patients who achieved PR/SD, the number of CD3 + , CD4 + T, and CD4 + /CD8 + indexes were significantly increased, whereas the number of CD8 + T lymphocytes was significantly decreased. Meanwhile, the 8 patients who achieved PD displayed different results. In addition, ROC curve combined detection of CD3 + , CD4 + , and CD8 + T [area under the curve (AUC) =0.9018, P<0.0001] showed good predictive ability for the efficacy of atezolizumab in advanced NSCLC. Conclusions Atezolizumab may alter the level of lymphocyte subsets in patients with advanced NSCLC, and the changes in lymphocyte subs...

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PD-1 blockade and CDK4/6 inhibition augment nonoverlapping features of T cell activation in cancer

Cited by 9 publications

References 52 publications

PD-1 Blockade Induces Reactivation of Nonproductive T-Cell Responses Characterized by NF-κB Signaling in Patients with Pancreatic Cancer

PD-1 Blockade Induces Reactivation of Nonproductive T-Cell Responses Characterized by NF-κB Signaling in Patients with Pancreatic Cancer

Blocking the CTLA-4 and PD-1 pathways during pulmonary paracoccidioidomycosis improves immunity, reduces disease severity, and increases the survival of infected mice

Changes in T lymphocyte subsets predict the efficacy of atezolizumab in advanced non-small cell lung cancer: a retrospective study

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