PD-1 blockade potentiates neoadjuvant chemotherapy in NSCLC via increasing CD127+ and KLRG1+ CD8 T cells
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ABSTRACT:
PROVIDER: PRJNA954049 | ENA |
REPOSITORIES: ENA
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Project description:The combination of PD-1 blockade with neoadjuvant chemotherapy (NAC) has achieved unprecedented clinical success in non-small-cell lung cancer (NSCLC) compared to NAC alone, but the underlying mechanisms by which PD-1 blockade augments the effects of chemotherapy remain incompletely elucidated. Single-cell RNA sequencing was performed on CD45+ immune cells isolated from surgically resected fresh tumor tissues of seven NSCLC patients receiving NAC or neoadjuvant pembrolizumab and chemotherapy (NAPC). Multiplex fluorescent immunohistochemistry was performed on paired FFPE tissues before and after NAC or NAPC from 65 resectable NSCLC patients, and results were validated with GEO dataset. NAC resulted in an increase only of CD20+ B cells, whereas NAPC increased the infiltration of CD20+ B cells, CD4+ T cells, CD4+CD127+ T cells, CD8+ T cells, CD8+CD127+ and CD8+KLRG1+ T cells. Synergistic increase in B and T cells promotes favorable therapeutic response after NAPC. Spatial distribution analysis discovered that CD8+ T cells and their CD127+ and KLRG1+ subsets were in closer proximity to CD4+ T/CD20+ B cells in NAPC versus NAC. GEO dataset validated that B-cell, CD4, memory and effector CD8 signatures correlated with therapeutic responses and clinical outcomes. The adding of PD-1 blockade to NAC promoted anti-tumor immunity through T and B cells recruitment in the tumor microenvironment and induced tumor-infiltrating CD8+ T cells skewed toward CD127+ and KLRG1+ phenotypes，which may be assisted by CD4+ T cells and B cells. Our comprehensive study identified key immune cell subsets exerting anti-tumor responses during PD-1 blockade therapy and that may be therapeutically targeted to improve upon existing immunotherapies for NSCLC.
2023-05-16 | GSE229353 | GEO
Project description:The combination of PD-1 blockade with neoadjuvant chemotherapy (NAC) has achieved unprecedented clinical success in non-small cell lung cancer (NSCLC) compared to NAC alone, but the underlying mechanisms by which PD-1 blockade augments the effects of chemotherapy remain incompletely elucidated. Single-cell RNA sequencing was performed on CD45+ immune cells isolated from surgically resected fresh tumors of seven NSCLC patients receiving NAC or neoadjuvant pembrolizumab and chemotherapy (NAPC). Multiplex fluorescent immunohistochemistry was performed on FFPE tissues before and after NAC or NAPC from 65 resectable NSCLC patients, and results were validated with GEO dataset. NAC resulted in an increase only of CD20+ B cells, whereas NAPC increased the infiltration of CD20+ B cells, CD4+ T cells, CD4+CD127+ T cells, CD8+ T cells, CD8+CD127+ and CD8+KLRG1+ T cells. Synergistic increase in B and T cells promotes favorable therapeutic response after NAPC. Spatial distribution analysis discovered that CD8+ T cells and their CD127+ and KLRG1+ subsets were in closer proximity to CD4+ T/CD20+ B cells in NAPC versus NAC. GEO dataset validated that B-cell, CD4, memory, and effector CD8 signatures correlated with therapeutic responses and clinical outcomes. The addition of PD-1 blockade to NAC promoted anti-tumor immunity through T and B cells recruitment in the tumor microenvironment and induced tumor-infiltrating CD8+ T cells skewed toward CD127+ and KLRG1+ phenotypes, which may be assisted by CD4+ T cells and B cells. Our comprehensive study identified key immune cell subsets exerting anti-tumor responses during PD-1 blockade therapy and that may be therapeutically targeted to improve upon existing immunotherapies for NSCLC.
| S-EPMC10213055 | biostudies-literature
Project description:The goal of this study is to characterize the transcriptional profile of three memory CD8 T cell subsets: IL-7Rα+KLRG1- (memory precursors, MP), IL-7Rα+KLRG1+ (KLRG1+ MP) and IL-7Rα-KLRG1+ (terminal effectors, TE).
2022-12-12 | GSE218777 | GEO
Project description:Background: Alternaria exposure is associated with severe asthma in humans. Alternaria exposure in mice potently activates group 2 innate lymphoid cells (ILC2s) via the IL-33/ST2 axis and causes ILC2s to robustly secrete type 2 cytokines. Objective: Our aim was to determine whether conventionally used ILC2 markers, ST2 (IL-33R) and CD127 (IL-7Ra), were sufficient to identify all Th2-cytokine producing ILCs after Alternaria exposure. Methods: Mice received intranasal Alternaria for three days prior to analysis. Lung ILCs were identified by flow cytometry as CD45+Lineage−Thy1.2+ lymphocyte-sized cells, divided into four subsets based on ST2 and CD127 expression, and stained for intracellular cytokines and transcription factors. Sort-purified ILC subpopulations were also analyzed by RNA sequencing and qPCR. Results: Alternaria exposure led to accumulation of all ILC populations regardless of ST2 or CD127 expression. Nearly half of the GATA-3+, IL-5+, and IL-13+ ILCs were “unconventional” as they were either single or double negative for ST2/CD127. Further, these populations upregulated CD25, KLRG1, and ICOS after Alternaria challenge. Some activated unconventional IL-5+ ILC2s also produced IFNγ and IL-17A. In addition to shared ILC2 transcripts (Gata3, Il5, Il13) in all populations, RNA-seq further identified novel transcripts enriched in each subset. Finally, transcripts from all populations that correlated best with IL-5 and IL-13 production included Tnfrsf18, Ffar2, and Pde4b. Conclusions: Unconventional ST2- and CD127-negative mouse lung ILC2 populations are induced by Alternaria. Thus, commonly used lung ILC2 identification methods based on ST2 and CD127 do not accurately account for the total ILC2 burden and may exclude nearly half of these cells.
2019-08-22 | GSE136156 | GEO
Project description:Recently, circulating multi- and uni-potential human ILC precursors (ILCP) have been found in a lymphocyte population that expresses CD117 and CD127 but lack CRTH2 and NKp44. However, these ILCPs have not been extensively characterized. We performed an unbiased Hierarchical Stochastic Neighbor Embedding (HSNE) analysis of the phenotype of peripheral blood CD117+ ILCPs which revealed the presence of three major subsets; the first expressed NKp46, the second expressed both NKp46 and CD56 and the third expressed KLRG1. Analysis of the differentiation potential of these cells on bulk and clonal levels, cytokine production and the transcriptome revealed that the NKp46+ ILCPs contain high frequencies of ILC3 precursors whereas a minority can differentiate into ILC1/NK-like cells. In contrast KLRG1+ ILCPs are biased to the ILC2 lineage, but are highly plastic and epigenetically poised to differentiate to other ILC subsets depending on the activation signals they receive.
2019-06-05 | GSE123817 | GEO
Project description:Recently, circulating multi- and uni-potent human ILC precursors (ILCP) have been found in a lymphocyte population that expresses CD117 and CD127 but lacks CRTH2 and NKp44. However, these ILCPs have not been extensively characterized. We performed an unbiased Hierarchical Stochastic Neighbor Embedding (HSNE) analysis of the phenotype of peripheral blood CD117+ ILCPs which revealed the presence of three major subsets: the first expressed NKp46, the second expressed both NKp46 and CD56, while the third expressed KLRG1. Analysis of their differentiation potential on bulk and clonal levels, cytokine production and the transcriptome revealed that the NKp46+ ILCPs contain high frequencies of ILC3 precursors whereas a minority can differentiate into ILC1/NK-like cells. In contrast, KLRG1+ ILCPs are biased to the ILC2 lineage, but are highly plastic and epigenetically primed to differentiate into other ILC subsets depending on the activation signals they receive.
2019-06-05 | GSE124054 | GEO
Project description:Clostridioides difficile CD127 Genome sequencing and assembly
| PRJNA85741 | ENA
Project description:Single cell transcriptomic analysis of human CD25+ CD127- CD4+ Treg cells and CD25- CD127+ CD4+ Tconv cells isolated from peripheral blood from two different donors
2018-03-15 | GSE111901 | GEO
Project description:To more specifically determine whether the TEC program is controlled by Notch, we generated molecular definitions of TECs and MPCs by whole transcriptome sequencing of sorted KLRG1-CD127+ and KLRG1+CD127- H-2 Db-NP specific CD8+ T cell populations from wild-type mice. These definitions were used to analyze data derived from RNAseq of splenic H-2 Db-NP+CD8+ T cells from WT and Notch1-2-KO mice 10 days post-infection with A/HKx31.
2014-10-26 | E-MTAB-2999 | biostudies-arrayexpress
Project description:Group 2 innate lymphoid cells (ILC-2s) regulate immune responses to pathogens, allergens, tissue remodeling and metabolic homeostasis in response to cytokines. Positive regulation of ILC-2s through ICOS has been recently elucidated but co-receptor mediated negative regulatory axis is yet to be defined. We demonstrate that PD-1 is an important negative regulator of KLRG1+ILC-2 function in both mice and humans. Increase in KLRG1+ ILC-2 cells numbers were attributed to an intrinsic defect in PD-1 signaling, which resulted in enhanced STAT5 activation. During Nippostrongylus brasiliensis infection, a significant expansion of KLRG1+ ILC-2 subsets occurred in pdcd1-/- mice and on adoptive transfer, pdcd1-/- KLRG1+ ILC-2s significantly reduced worm burden. Furthermore, blocking antibody to PD-1 increased KLRG1+ ILC-2 cell number and reduced disease burden. Therefore PD-1 is an important negative regulator and is vital for maintaining the number and hence function of KLRG1+ ILC-2s.
2017-05-04 | GSE94609 | GEO