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4-1BB+ Tregs and inhibitory progenitor exhausted T cells confer resistance to anti-PD-L1 and anti-CTLA-4 combination therapy

ABSTRACT: Predictors of immune checkpoint inhibitor (ICI) response among cancer patients are unclear despite active research into their tumor microenvironment. Moreover, mechanisms of combinatory ICI treatment are not understood, leading to ineffective clinical trials. There is currently an urgent need to stratify and select cancer patients for implementing successful immunotherapy. In this study we leverage the advantages of neoadjuvant immunotherapy phase II window of opportunity study, collecting paired samples of Durvalumab or Durvalumab and Tremelimumab treated head and neck cancer patients. Single-cell multi-omics profiling of TCR or RNA was performed for 57 biopsies including paired baseline prior to ICI treatment and were annotated for early ICI pathologic response. Samples were analyzed using state-of-the-art bioinformatic approaches using non-negative matrix factorization (NMF), cell-type specific gene networks, and a transformer-based foundation model. We found signatures associated with ICI sensitivity and immune activation that predict ICI response at baseline, validated using foundation model pretrained on millions of single cells. Moreover, we found that Tremelimumab therapy effect is inhibited via upregulation of IL2 signaling by 4-1BB+ (TNFRSF9+) regulatory T cells, and ICI response is distinguished by 4-1BB activity of effector CD8+ T cells. Importantly, we report a novel subset of tumor-specific precursor exhausted CD8+ T (Tpex) state distinguished with high expression of KLRB1 and IL17R that is associated with ICI resistance. The balance of the heterogeneous precursor subsets predicts immunotherapy response for multiple cancer types. Our findings provide important cellular and genetic insights into the immunological bases for predicting response via malignant-CD8+ T cell axis. Evidence of transcriptional regulation governing Tpex transition toward immune suppression necessitates future development of clinical strategies for maintaining ICI response and suppressing relapse.

ORGANISM(S): Homo sapiens

PROVIDER: GSE286827 | GEO | 2025/09/02

REPOSITORIES: GEO

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Project description:The activation of TLR-MyD88 (Toll like receptor- Myeloid differentiation factor 88) signaling within T cells functions as a potent costimulatory signal that boosts antitumor and antiviral responses. However, the molecular mechanisms underlying the costimulatory processes are poorly understood. We compared microarray gene analysis data between TLR1-TLR2 stimulated and unstimulated T cell receptor transgenic âpmelâ and MyD88-/-pmel CD8+ T cells and identified changes in the expression levels of several TNF family members. In particular, TLR-stimulation increased 4-1BB levels in pmel but not in MyD88-/-pmel T cells. A link between 4-1BB and TLR1-TLR2 signaling in CD8+ T cells was highlighted by in fact that 4-1BB-/- T cells exhibited suboptimal responses to TLR1-TLR2 agonist, but responded normally to CD28 or OX40 costimulation. Moreover, blocking 4-1BB signaling with antibodies also hindered the costimulatory effects of the TLR1-TLR2 agonist. The elevated levels of 4-1BB transcripts in TLR1-TLR2âstimulated cells were not due to increased mRNA stability nor increased histone activation but instead were associated with increased binding of p65 and c-Jun to two distinct 4-1BB promoter sites. Combining TLR1-TLR2 ligand with an agonistic anti-4-1BB antibody enhanced the antitumor activity in mice with established melanoma tumors. These studies reveal that the costimulatory effects of TLR1-TLR2 signaling in CD8+ T cells are in part mediated by 4-1BB and are important for mounting an effective antitumor immune response. CD8+ T cells from the B6.Cg-Thy1/Cy Tg(TcraTcrb)8Rest/J mice, referred to as âpmelâ T cells or from MyD88 knockout pmel mice (MyD88â/âpmel) were sorted. pmel and MyD88â/âpmel T cells were activated using MyD88â/â CD8 T cell-depleted splenocytes pulsed with 10ng/ml of mgp100. This was with or without 10Âµg/ml of Pam3CSK4. pmel or MyD88â/âpmel CD8 T cells were enriched and used for the extraction of RNA used for genomic analysis.

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4-1BB+ Tregs and inhibitory progenitor exhausted T cells confer resistance to anti-PD-L1 and anti-CTLA-4 combination therapy

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