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Differential T cell clonal dynamics underlie outcomes to frontline chemoimmunotherapy in advanced gastric cancer [paired scRNA/TCR-seq]

ABSTRACT: The addition of aPD1 to 5-FU/platinum in advanced gastric cancer (GC) yields variable responses. To understand cooperativity between chemotherapy and immunotherapy, we previously reported a phase II trial sequentially adding pembrolizumab to 5-FU/platinum. In this study, we use single-cell RNA- and TCR-sequencing to analyze 66,813 T cells from primary tumor biopsies pre-treatment, post-chemotherapy, and post-immunotherapy in 33 patients. We observed greater abundance, persistence, and recruitment of T cells with predicted tumor-reactivity in patients with prolonged progression-free survival (slow progressors). Increased B cell abundance and predicted B cell to T cell interactions supported T cell memory and co-stimulation, providing a mechanism for increased abundance and persistence of progenitor-exhausted and tumor-reactive T cells in slow progressors. T cell clones emerging in the tumor after immunotherapy were in the blood before treatment only in slow progressors. Our study thus highlights pre-treatment and early chemotherapy-induced T cell dynamics and B cell to T cell interactions that may drive durable response to chemoimmunotherapy in GC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE315928 | GEO | 2026/04/01

REPOSITORIES: GEO

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Differential T cell clonal dynamics underlie outcomes to frontline chemoimmunotherapy in advanced gastric cancer [TCR-seq]

Project description:The addition of aPD1 to 5-FU/platinum in advanced gastric cancer (GC) yields variable responses. To understand cooperativity between chemotherapy and immunotherapy, we previously reported a phase II trial sequentially adding pembrolizumab to 5-FU/platinum. In this study, we use single-cell RNA- and TCR-sequencing to analyze 66,813 T cells from primary tumor biopsies pre-treatment, post-chemotherapy, and post-immunotherapy in 33 patients. We observed greater abundance, persistence, and recruitment of T cells with predicted tumor-reactivity in patients with prolonged progression-free survival (slow progressors). Increased B cell abundance and predicted B cell to T cell interactions supported T cell memory and co-stimulation, providing a mechanism for increased abundance and persistence of progenitor-exhausted and tumor-reactive T cells in slow progressors. T cell clones emerging in the tumor after immunotherapy were in the blood before treatment only in slow progressors. Our study thus highlights pre-treatment and early chemotherapy-induced T cell dynamics and B cell to T cell interactions that may drive durable response to chemoimmunotherapy in GC.

2026-04-01 | GSE315929 | GEO

Expression data from oxaliplatin-treated tumors from mice pre-treated or not with antibiotics cocktail

Project description:The gut microbiota influences both local and systemic inflammation. Inflammation contributes to development, progression and treatment of cancer, but it remains unclear whether commensal bacteria affect inflammation in the sterile tumor microenvironment. Here we show that disruption of the microbiota impairs the response of subcutaneous tumors to CpG-oligonucleotide immunotherapy and platinum chemotherapy. In antibiotic-treated or germ-free mice, tumor-infiltrating myeloid-derived cells responded poorly to therapy, resulting in lower cytokine production and tumor necrosis after CpG-oligonucleotide treatment, and deficient production of reactive oxygen species and cytotoxicity following chemotherapy. Thus, optimal responses to cancer therapy require an intact commensal microbiota that mediates its effects by modulating myeloid-derived cell functions in the tumor microenvironment. These findings underscore the importance of the microbiota in the outcome of disease treatment. Oxaliplatin treatment induces expression of pro-inflammatory genes, which are inhibited by antibiotic pretreatment. Our goal was to ascertain the effect of antibiotic on the tumor gene expression profile prior to treatment and early on after the treatment with chemotherapy (oxaliplatin). The time points were selected t

2013-12-03 | E-GEOD-51414 | biostudies-arrayexpress

Reducing Dietary Protein Enhances the Anti-tumor Effects of Chemotherapy

Project description:Diet is believed to be an important mediator of oncogenesis and response to anti-cancer therapies, although, no evidence-based dietary guidelines exist for patients with cancer. Limiting protein intake can suppress tumor growth by both inducing nutrient stress and enhancing anti-tumor immunity. However, little is known about the impact of reducing dietary protein on the efficacy of standard anti-cancer therapies, including chemotherapy. Here, we present evidence that reducing protein intake in mice by 50% essentially stops the growth of established tumors, in parallel with inducing a stress response and DNA damage. Further, a reduced protein diet markedly enhances tumor regression upon treatment with 5-fluorouracil (5-FU), accompanied by elevated apoptosis and suppressed mitosis of tumor cells. Proteomic analysis of tumors from 5-FU treated mice fed control or reduced protein diets revealed marked changes including decreased abundance of proteins that mediate DNA repair and replication in mice given diet with reduced protein. In vitro studies mimicking amino acid changes found in tumors from reduced protein-fed mice revealed that cell viability and proliferation rates were similar irrespective of amino acid levels in medium, following 5-FU treatment. In contrast, cGAS-STING signaling, including transcription of Interferon beta 1, was maximally increased in 5-FU treated cells cultured in modified amino acid medium. These findings correlated with enhanced immune cell influx into tumors from mice fed reduced protein diet following 5-FU administration. Collectively, these findings suggest that reducing dietary protein in cancer patients may enhance the efficacy of chemotherapy, which may be mediated by anti-tumor immunity.

2025-03-07 | PXD052110 | Pride

Comprehensive testing of chemotherapy and immune checkpoint blockade in preclinical cancer models identifies additive combinations

Project description:Background: Antibodies that target immune checkpoints such as cytotoxic T lymphocyte antigen 4 (CTLA 4) and the programmed cell death protein 1/ligand 1 (PD-1/PD-L1) are now a treatment option for multiple cancer types. However, as a monotherapy, objective responses only occur in a minority of patients. Chemotherapy is widely used in combination with immune checkpoint blockade (ICB). Although a variety of isolated immunostimulatory effects have been reported for several classes of chemotherapeutics, it is unclear which chemotherapeutics provide the most benefit when combined with ICB. Methods: We investigated 10 chemotherapies from the main canonical classes dosed at the clinically relevant maximum tolerated dose in combination with anti CTLA-4/anti-PD-L1 ICB. We screened these chemo-immunotherapy combinations in two murine mesothelioma models from two different genetic backgrounds, and identified chemotherapies that produced additive, neutral or antagonistic effects when combined with ICB. Using flow cytometry and bulk RNAseq, we characterized the tumor immune milieu in additive chemo-immunotherapy combinations. Results: 5-fluorouracil (5-FU) or cisplatin were additive when combined with ICB while vinorelbine and etoposide provided no additional benefit when combined with ICB. The combination of 5-FU with ICB augmented an inflammatory tumor microenvironment with markedly increased CD8+ T cell activation and upregulation of IFN , TNF and IL-1β signaling. The effective anti tumor immune response of 5-FU chemo-immunotherapy was dependent on CD8+ T cells but was unaffected when TNF or IL 1β cytokine signaling pathways were blocked. Conclusions: Our study identified additive and non-additive chemotherapy/ICB combinations and suggests a possible role for increased inflammation in the tumor microenvironment as a basis for effective combination therapy.

2022-05-02 | GSE188481 | GEO

Multi-level proteomics identifies CT45 as a chemosensitivity mediator and immunotherapy target in ovarian cancer

Project description:Most high-grade serous ovarian cancer (HGSOC) patients develop resistance to platinum-based chemotherapy and recur, but 15% remain disease-free over a decade. To discover drivers of long-term survival, we quantitatively analyzed the proteomes of platinum resistant and sensitive HGSOC patients from minute amounts of formalin-fixed, paraffin-embedded tumors. This revealed cancer/testis antigen 45 (CT45) as an independent prognostic factor associated with a doubling of disease-free survival in advanced stage HGSOC. Phospho- and interaction proteomics tied CT45 to DNA damage pathways through direct interaction with the PP4 phosphatase complex. In vitro, CT45 regulated PP4 activity and its high expression led to increased DNA damage and platinum sensitivity. CT45-derived HLA class I peptides, identified by immunopeptidomics, activate patient-derived cytotoxic T cells and promote tumor cell killing. This study highlights the power of clinical cancer proteomics to identify targets for chemo- and immunotherapy and illuminate their biological roles.

2020-04-19 | PXD010372 | Pride

Intratumor transforming growth factor-β signaling with extracellular matrix-related gene regulation marks chemotherapy-resistant gastric cancer

Project description:Drug-tolerant persister (DTP) cells remain following chemotherapy and can cause cancer relapse. However, it is unclear when acquired resistance to chemotherapy emerges. Here, we compared the gene expression profiles of gastric cancer patient-derived cells (GC PDCs) and their respective xenograft tumors with different sensitivities to 5-fluorouracil (5-FU) by using immunodeficient female BALB/c-nu mice. RNA sequencing analysis of 5-FU-treated PDCs demonstrated that DNA replication/cell cycle-related genes were transiently induced in the earlier phase of DTP cell emergence, while extracellular matrix (ECM)-related genes were sustainably upregulated during long-term cell survival in 5-FU-resistant residual tumors. NicheNet analysis, which uncovers cell-cell signal interactions, indicated the transforming growth factor-β (TGF-β) pathway as the upstream regulator in response to 5-FU treatment. This induced ECM-related gene expression in the 5-FU-resistant tumor model. In the 5-FU-resistant residual tumors, there was a marked upregulation of cancer cell-derived TGF-β1 expression and increased phosphorylation of SMAD3, a downstream regulator of the TGF-β receptor. By contrast, these responses were not observed in a 5-FU-sensitive tumor model. We further found that TGF-β-related upregulation of ECM genes was preferentially observed in non-responders to chemotherapy with 5-FU and/or oxaliplatin among 22 patient-derived xenograft tumors. These observations suggest that chemotherapy-induced activation of the TGF-β1/SMAD3/ECM-related gene axis is a potential biomarker for the emergence of drug resistance in GCs.

2024-05-30 | GSE264144 | GEO

Detection of mitochondrial DNA mutations in T cells following 5-FU or cisplatin exposure

Project description:T cells are pivotal to cancer immunotherapy, yet chemotherapy may erode their fitness. Using a single-cell technique, we show that exposure to two widely used chemotherapeutic agents, 5-FU (5-fluorouracil) and cisplatin, induces non-synonymous mitochondrial DNA mutations (mtDNA) in T cells. Notably, nearly all detected mtDNA mutations are transition mutations. Like the effects observed in genomic DNA mutations, the impacts of mtDNA mutations in T cells appear to be random. Some T cells with mtDNA mutations concentrate in clusters associated with gene markers, while others do not. Additionally, several mtDNA mutations are found in the fraction of treated T cells with low mitochondrial activity, suggesting their potential effect on mitochondrial function. Importantly, mtDNA mutations are detected in tumor-infiltrating T cells from patients with colorectal cancer who received chemotherapy. Our findings uncover an unappreciated consequence of chemotherapy on T cell mitochondria, and these results raise concerns about administering immunotherapy and chemotherapy concurrently.

2026-01-27 | GSE310683 | GEO

Synergistic effects of 5-Fluorouracil in combination with Salinomycin promoted ferroptosis via inhibiting SLC7A11/GPX4 in Colorectal Cancer

Project description:5-FU resistance is considered to be a possible reason for the failure of conventional drug treatment of colorectal cancer (CRC). Recently, salinomycin (SAL), as a selective inhibitor of cancer stem cells (CSCs), has been used to sensitize and attenuate a variety of solid tumor chemotherapy drugs. In our study, our goal was to combine SAL with 5-FU to explore whether increase the sensitivity of CRC to 5-FU and the molecular mechanism that involved in enhancing 5-FU sensitivity and promoting tumor cell chemotherapeutic death.

2025-06-10 | GSE298808 | GEO

Proinflammatory isoforms of IL-32 as novel and robust biomarkers for control failure in HIV-infected slow-progressors.

2015-12-31 | GSE74790 | GEO

Proinflammatory isoforms of IL-32 as novel and robust biomarkers for control failure in HIV-infected slow-progressors.

Project description:HIV-infected slow-progressors (SP) represent a heterogeneous group of subjects who spontaneously control HIV infection without treatment for several years while showing moderate signs of disease progression. Here we determined the frequency of SP subjects who showed loss of HIV control within our Canadian Cohort of HIV+ Slow-Progressors and identified the proinflammatory cytokine IL-32 as a robust biomarker for control failure. Total cellular RNA was extracted from PBMC from 5 donors at two time points ('V1' before and 'V2' after loss of control, and only Long Term Non Progressors (LTNP) were part of the case study), along with 2 control Leuka914 and Aging106032 samples.

2015-12-31 | E-GEOD-74790 | biostudies-arrayexpress

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