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RELB Reprograms Exhausted Tumor-Infiltrating Lymphocytes for Improved Adoptive Cell Therapy [TCR-Seq]

ABSTRACT: Tumor-infiltrating lymphocytes (TILs) are a promising autologous cell therapy to treat solid tumors. TILs are manufactured by expanding and reinfusing tumor-reactive T cells from tumor biopsies. Efficacy of TIL therapies has been limited by the heterogeneity of expanded TIL products and the high prevalence of dysfunctional exhausted CD8+ T cells (TEX). A subset of CD8+ TILs that are double-positive (DP) for CD103 and CD39 is enriched for tumor-reactive TILs across multiple cancer types, but also is susceptible to the TEX state. We screened overexpression of all human transcription factors (TFs) to discover master regulators of expansion in DP TILs from non-small cell lung cancer patients. RELB emerged as the dominant hit driving proliferation of DP TILs despite exhaustion induced by repeat stimulation, with a skew towards CD8+ cells. TCR-seq showed maintenance of TCR diversity from the initial TCR repertoire after multiple days of in vitro expansion driven by RELB. Transcriptome profiling of multiple RELB-expressing TIL subtypes revealed a shift towards a memory/costimulatory-like phenotype. Using a HER2-targeting CAR and tumor co-culture model, RELB conferred improved persistence after multiple tumor challenges in vitro and improved solid tumor control in mouse xenografts in vivo. Finally, co-culture of RELB-overexpressing TILs with patient-matched tumor organoids showed an increase in TIL product polyfunctionality, tumor reactivity, and tumor killing.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303438 | GEO | 2025/12/02

REPOSITORIES: GEO

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RELB Reprograms Exhausted Tumor-Infiltrating Lymphocytes for Improved Adoptive Cell Therapy [RNA-Seq]

Project description:Tumor-infiltrating lymphocytes (TILs) are a promising autologous cell therapy to treat solid tumors. TILs are manufactured by expanding and reinfusing tumor-reactive T cells from tumor biopsies. Efficacy of TIL therapies has been limited by the heterogeneity of expanded TIL products and the high prevalence of dysfunctional exhausted CD8+ T cells (TEX). A subset of CD8+ TILs that are double-positive (DP) for CD103 and CD39 is enriched for tumor-reactive TILs across multiple cancer types, but also is susceptible to the TEX state. We screened overexpression of all human transcription factors (TFs) to discover master regulators of expansion in DP TILs from non-small cell lung cancer patients. RELB emerged as the dominant hit driving proliferation of DP TILs despite exhaustion induced by repeat stimulation, with a skew towards CD8+ cells. TCR-seq showed maintenance of TCR diversity from the initial TCR repertoire after multiple days of in vitro expansion driven by RELB. Transcriptome profiling of multiple RELB-expressing TIL subtypes revealed a shift towards a memory/costimulatory-like phenotype. Using a HER2-targeting CAR and tumor co-culture model, RELB conferred improved persistence after multiple tumor challenges in vitro and improved solid tumor control in mouse xenografts in vivo. Finally, co-culture of RELB-overexpressing TILs with patient-matched tumor organoids showed an increase in TIL product polyfunctionality, tumor reactivity, and tumor killing.

2025-12-02 | GSE303432 | GEO

RELB Reprograms Exhausted Tumor-Infiltrating Lymphocytes for Improved Adoptive Cell Therapy [proliferation]

2025-12-02 | GSE303442 | GEO

scRNA and TCRalpha-beta-seq data from 3 dissociated renal cell carcinoma samples that were CD45 positive sorted, enriched for lymphocytes and sequenced

Project description:In our study, we have characterized the non-expanded and expanded tumor-infiltrating lymphocytes (TILs) from treatment-naive renal cell carcinoma (RCC) patients (n=3), as well as the minimally cultured pre-REP TILs and rapidly expanded REP TILs with a clinical-grade TIL expansion protocol. We observed that the REP TILs encompassed an abundance of CD4positive T-cells, together with increased LAG-3 and low PD-1 expression in the CD4positive and CD8positive T-cells. In addition, we observed that the TIL expansion protocol expanded small CD4positive T-cell clonotypes in the tumor microenvironment (TME), and that the large, exhausted tumor T-cell clonotypes do not expand. We further identified RCC-associated TCR motifs that were validated in multiple TCRalpha-beta-seq and scRNAand TCRalpha-beta-seq datasets, as well as quantified the RCC-associated TCRs from the REP protocol. Overall, the T-cells carrying the RCC-associated TCRs remained high in the tumors and corresponding pre-REP TILs, but the frequency was reduced in the REP TILs. Furthermore, the overall anti-viral TCRs remained low throughout the REP protocol. Our results provide an in-depth understanding of the origin, immunophenotype, and specificity of the TCRs in RCC TILs.

2023-12-29 | E-MTAB-12910 | biostudies-arrayexpress

Chronic Type I interferons signaling promotes lipid peroxidation-driven terminal CD8+T cell exhaustion and curtails anti-PD-1 treatment efficacy [RNA-Seq]

Project description:Identifying signals that govern the differentiation of tumor-infiltrating CD8 + T cells (CD8 + TILs) towards exhaustion can improve current therapeutic approaches for cancer. Here, we show that type I interferons (IFN-Is) act as environmental cues enhancing terminal CD8 + T cell exhaustion in tumors. We found enrichment of IFNIs-stimulated genes (ISGs) within exhausted CD8 + T cells (Tex cells) in patients across various cancer types, with heightened ISG levels correlating with poor response to immune checkpoint blockade (ICB) therapy. In preclinical models, CD8 + TILs devoid of IFN-Is signaling developed less exhaustion features, provided better tumor control and showed greater response to ICB-mediated rejuvenation. Mechanistically, chronic IFN-Is stimulation perturbed lipid metabolism and redox balance in Tex cells, leading to aberrant lipid accumulation and elevated oxidative stress. Collectively, these defects promoted lipid peroxidation, which potentiated metabolic and functional exhaustion of Tex cells. Thus, cell intrinsic IFN-Is signaling regulates the extent of CD8+ TIL exhaustion, and has important implications for immunotherapy.

2022-11-16 | GSE212697 | GEO

Chronic Type I interferons signaling promotes lipid peroxidation-driven terminal CD8+T cell exhaustion and curtails anti-PD-1 treatment efficacy

2022-11-16 | GSE212699 | GEO

Chronic Type I interferons signaling promotes lipid peroxidation-driven terminal CD8+T cell exhaustion and curtails anti-PD-1 treatment efficacy [ATAC-Seq]

2022-11-16 | GSE212698 | GEO

CD8+ TILs in NSCLC differentiate into TEMRA via a bifurcated trajectory, deciphering immunogenicity of tumor-antigens

Project description:CD8+ tumor-infiltrating lymphocytes (TILs) comprise phenotypically and functionally heterogeneous subpopulations. Of these, effector memory CD45RA-expressing CD8+ T cells (Temra) have been discovered and characterized as the most terminally differentiated subset. However, their exact ontogeny and physiological importance in association with tumor progression remain poorly understood. We analyzed primary tumors and peripheral blood samples from 26 patients with non-small cell lung cancer and analyzed their phenotypes and functional characteristics using flow cytometry, RNA-sequencing, and bioinformatics. We found that tumor-infiltrating Temra (tilTemra) cells largely differ from peripheral blood Temra (pTemra), with distinct transcriptomes and functional properties. Notably, although majority of the pTemra was CD27-CD28- double-negative (DN), a large fraction of tilTemra population was CD27+CD28+ double-positive (DP), a characteristic of early-stage, less differentiated effector cells. Trajectory analysis revealed that CD8+ TILs undergo a divergent sequence of events for differentiation into either DP or DN tilTemra. Such a differentiation toward DP tilTemra relied on persistent expression of CD27 and CD28 and was associated with weak T cell receptor engagement. Thus, a higher proportion of DP Temra was correlated with lower immunogenicity of tumor antigens and consequently lower accumulation of CD8+ TILs. These data suggest a complex interplay between CD8+ T cells and tumors and define DP Temra as a unique subset of tumor-specific CD8+ TILs that are produced in patients with relatively low immunogenic cancer types, predicting immunogenicity of tumor antigens and CD8+ TIL counts, a reliable biomarker for successful cancer immunotherapy.

2021-09-14 | GSE184053 | GEO

Checkpoint blockade induced CD8+ T cell differentiation in responders in head and neck cancers

Project description:Background: Outcomes for locally advanced or recurrent/ metastatic head and neck squamous cell carcinomas (HNSCCs) remain unfavorable despite recent advances with immune checkpoint blockade (ICB). Preclinical studies using model antigens identified a critical role of CD8+TCF7+PD1+ T cells in anti-PD1 response. Studies on the heterogeneity and clonal dynamics of global tumor infiltrating T lymphocytes (TILs) in the HNSCC anti-PD1 and anti-CTLA4 response have not been explored. Results: In this study, we generated isogenic HNSCC anti-PD1 sensitive/resistant models that bore distinct cancer cell intrinsic transcriptomic programs. Tumor microenvironment characterization using mass cytometry and targeted depletion revealed the contribution of Tregs and M2-like macrophages in anti-PD1 resistance. Paired single-cell RNA and TCR sequencing on tumor infiltrating immune cells from ICB responsive and resistant HNSCC models identified a spectrum of CD8+ TIL subsets including TCF7+PD1- (naïve/memory-like), TCF7+PD1+ (progenitor exhausted), and TCF7-PD1+ (terminally exhausted). Mapping TCR shared fractions between these subsets identified that successful anti-PD1 or anti-CTLA4 therapy induced higher post-treatment T cell lineage transitions. A TIL differentiation gene signature was associated with better responses in multiple ICB clinical trials. Conclusions: Together, analyses integrating scRNAseq and TCRseq demonstrate distinct differentiation dynamics of CD8+ TILs in novel ICB responsive and resistant HNSCC models, highlighting critical aspects of CD8+ TIL differentiation in response to ICB.

2021-12-01 | GSE153383 | GEO

Tumor infiltrating exhausted CD8+ T cells dictate divergent survival outcomes in pre- versus post-menopausal estrogen receptor-positive breast cancer

Project description:CD8+ tumor infiltrating lymphocytes (TILs) are associated with improved survival in triple negative breast cancer (TNBC), yet have no association with survival in estrogen receptor-positive (ER+) BC. The basis for these contrasting findings remains elusive. We identify subsets of BC tumors infiltrated by CD8+ T cells with characteristic features of exhausted T cells (TEX). Tumors with abundant CD8+ TEX exhibit a distinct tumor microenvironment marked by amplified interferon-γ signaling related pathways and higher PD-L1 expression. Paradoxically, high levels of CD8+ TEX TILs associate with decreased overall survival ER+ BC patients, but not TNBC patients. Moreover, high tumor expression of a CD8+ TEX signature identifies dramatically reduced survival in pre-menopausal, but not post-menopausal, ER+ BC patients. Finally, we demonstrate the value of a tumor TEX signature score in identifying high-risk pre-menopausal ER+ BC patients amongst those with intermediate Oncotype Dx breast recurrence scores. Our data highlight the complex relationship between CD8+ TILs, interferon-γ signaling, and estrogen receptor status in BC patient survival. This work identifies pre-menopausal ER+ BC patients with high levels of tumor infiltrating CD8+ TEX as a high-risk subset that may benefit from immunotherapy strategies.

2022-02-23 | GSE190202 | GEO

Tumor-reactive T cell clonotype dynamics underlying clinical response to TIL therapy in melanoma [multiome]

Project description:Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon in vitro expansion, yielding products enriched in tumor-specific CD8+ cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization.

2024-09-13 | GSE261023 | GEO

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