Tumor-intrinsic sensitivity to the pro-apoptotic effects of IFN-γ is a major determinant of CD4+ CAR T-cell antitumor activity

Boulch, Morgane; Cazaux, Marine; Cuffel, Alexis; Guérin, Marion V.; Garcia, Zacarias; Alonso, Ruby; Lemaı̂tre, Fabrice; Beer, Alexander; Corre, Béatrice; Menger, Laurie; Grandjean, Capucine L.; Morin, Florence; Thiéblemont, Catherine; Caillat‐Zucman, Sophie; Bousso, Philippe

doi:10.1038/s43018-023-00570-7

Cited by 45 publications

(23 citation statements)

References 71 publications

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“…Activated T cells secrete Interleukin 2 (IL-2), which promotes the proliferation and differentiation of T cells [ 25 , 26 ]. Interferon-γ (IFN-γ) is secreted by activated T cells and exerts anti-tumor effects [ 27 ]. In order to detect the effect of IGFBP3 on Jurkat cells activation, we measured the mRNA expression of IL-2 and IFN-γ in Jurkat cells after co-culture with IGFBP3 overexpressing cells.…”

Section: Resultsmentioning

confidence: 99%

IGFBP3 induces PD-L1 expression to promote glioblastoma immune evasion

Zhao,

Wang,

et al. 2024

Cancer Cell Int

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Background Glioblastoma (GBM) characterized by immune escape is the most malignant primary brain tumors, which has strong immunosuppressive effect. Programmed death ligand-1 (PD-L1) is a recognized immunosuppressive member on the surface of tumor cells, and plays a crucial role in immune evasion of tumors. Actually, little is known about the regulation of PD-L1 expression in GBM. Insulin-like growth factor binding protein 3 (IGFBP3) is upregulated in GBM and is related to poor patient prognosis. However, it remains unclear whether IGFBP3 plays a role in the regulation of PD-L1 expression in GBM. Methods The role of IGFBP3 in the glioma immune microenvironment was investigated using the CIBERSORT algorithm. The correlation between IGFBP3 and PD-L1 expression was analyzed using TCGA and CGGA databases. QRT-PCR, immunoblotting and RNA-seq were used to examine the regulatory effect of IGFBP3 on PD-L1 expression. Co-culture assay, cell counting kit (CCK-8), qRT-PCR, ELISA and flow cytometry were performed to explore the function of IGFBP3 in inducing immunosuppression. The biological role of IGFBP3 was verified using immunohistochemical, immunofluorescence and mice orthotopic tumor model. Results In this study, we analyzed immune cells infiltration in gliomas and found that IGFBP3 may be associated with an immunosuppressive microenvironment. Then, by analyzing TCGA and CGGA databases, our results showed that IGFBP3 and PD-L1 expression were positively correlated in GBM patients, but not in LGG patients. In vitro experiments conducted on different GBM cell lines revealed that the overexpression of IGFBP3 led to an increase in PD-L1 expression, which was reversible upon knockdown IGFBP3. Mechanistically, IGFBP3 activated the JAK2/STAT3 signaling pathway, leading to an increase in PD-L1 expression. Additionally, co-culture experiments results showed IGFBP3 overexpression induced upregulation of PD-L1 expression promoted apoptosis in Jurkat cells, and this effect was blocked by IGFBP3 antibody and PDL-1 inhibitors. Importantly, in vivo experiments targeting IGFBP3 suppressed tumor growth and significantly prolonged the survival of mice. Conclusions This research demonstrated IGFBP3 is a novel regulator for PD-L1 expression in GBM, and identified a new mechanism by which IGFBP3 regulates immune evasion through PD-L1, suggesting that IGFBP3 may be a potential novel target for GBM therapy.

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Section: Resultsmentioning

confidence: 99%

IGFBP3 induces PD-L1 expression to promote glioblastoma immune evasion

Zhao,

Wang,

et al. 2024

Cancer Cell Int

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“…The 10F04mc TCR, which is a type II HLA molecular-restricted TCR, has been transduced into both CD4 + and CD8 + T cells, and both types of T cells have shown functional anti-tumor activity. CD4 + T cells transduced with 10F04mc TCR not only secret cytokines such as IFNγ, TNFα, and IL-2 but also secret high levels of Granzyme B, indicating their potential to exert cytotoxic functions 41 – 43 . The multifunctional of 10F04 TCR in both CD4 + and CD8 + T cells may explain its superior antitumor activity.…”

Section: Discussionmentioning

confidence: 99%

HLA-class II restricted TCR targeting human papillomavirus type 18 E7 induces solid tumor remission in mice

Long,

Chen,

et al. 2024

Nat Commun

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T cell receptor (TCR)-engineered T cell therapy is a promising potential treatment for solid tumors, with preliminary efficacy demonstrated in clinical trials. However, obtaining clinically effective TCR molecules remains a major challenge. We have developed a strategy for cloning tumor-specific TCRs from long-term surviving patients who have responded to immunotherapy. Here, we report the identification of a TCR (10F04), which is human leukocyte antigen (HLA)-DRA/DRB1*09:01 restricted and human papillomavirus type 18 (HPV18) E784-98 specific, from a multiple antigens stimulating cellular therapy (MASCT) benefited metastatic cervical cancer patient. Upon transduction into human T cells, the 10F04 TCR demonstrated robust antitumor activity in both in vitro and in vivo models. Notably, the TCR effectively redirected both CD4+ and CD8+ T cells to specifically recognize tumor cells and induced multiple cytokine secretion along with durable antitumor activity and outstanding safety profiles. As a result, this TCR is currently being investigated in a phase I clinical trial for treating HPV18-positive cancers. This study provides an approach for developing safe and effective TCR-T therapies, while underscoring the potential of HLA class II-restricted TCR-T therapy as a cancer treatment.

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“…Meanwhile, it was further revealed that CD4+T cells, in conjunction with IFN-activated mononuclear phagocytes, collectively instigated an indirect inflammatory process resulting in tumor cell death ( 18 ).. In recent years, CAR-T technology has been used to modify CD4+ T cells, and anti-tumor ability does not depend on cytotoxicity, but indirectly acts on tumor cells through the production of interferon-γ (IFN-γ), a large area and a long distance ( 19 ). In addition, the successful application of Adoptive cell transfer (ACT) immunotherapy with CD4+T cells in clinical research holds immense significance for the prospective treatment of cancer patients, undoubtedly paving the way for advancements in future therapies.…”

Section: Discussionmentioning

confidence: 99%

A Mendelian analysis of the relationships between immune cells and breast cancer

Wang,

Gao,

Zeng

et al. 2024

Front. Oncol.

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BackgroundEmerging evidence showed immune cells were associated with the development of breast cancer. Nonetheless, the causal link between them remains uncertain. Consequently, the objective of this study was to investigate the causal connection between immune traits and the likelihood of developing breast cancer.MethodsA two-sample Mendelian randomization (MR) analysis was conducted to establish the causal relationship between immune cells and breast cancer in this study. Utilizing publicly accessible genetic data, we investigated causal connections between 731 immune cells and the occurrence of breast cancer. The primary approach for exploring this relationship was the application of the inverse-variance-weighted (IVW) method. Furthermore, sensitivity analyses, encompassing the leave-one-out analysis, Cochran Q test, and Egger intercept test were performed to validate the reliability of the Mendelian randomization results. Finally, we used Bayesian Weighted Mendelian Randomization (BWMR) approach to test the results of MR study.ResultsAccording to the Bonferroni correction, no immune trait was identified with a decreased or increased risk of overall breast cancer risk. As for the ER+ breast cancer, 6 immune trait was identified after the Bonferroni method. the IVW method results showed that CD45RA- CD4+ %CD4+ (p-value:1.37×10−6), CD8dim %T cell (p-value:4.62×10−43), BAFF-R on IgD+ CD38- unsw mem (p-value:6.93×10−5), CD27 on PB/PC (p-value:2.72×10−18) lowered the risk of breast cancer. However, CD19 on IgD- CD38br (p-value:1.64×10−6), CD25 on IgD+ CD38dim (p-value: - ∞) were associated with a higher risk of developing breast cancer. As for the CX3CR1 on CD14+ CD16- monocyte (p-value: 1.15×10−166), the IVW method clearly demonstrated a protective effect against ER- breast cancer. For the above positive results, BAFF-R on IgD+ CD38- unsw mem was the sole association linked to reduced breast cancer risk using the BWMR method. The intercept terms’ p-values in MR-Egger regression all exceeded 0.05, indicating the absence of potential horizontal pleiotropy.ConclusionThrough genetic approaches, our study has illustrated the distinct correlation between immune cells and breast cancer, potentially paving the way for earlier diagnosis and more efficient treatment alternatives.

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Tumor-intrinsic sensitivity to the pro-apoptotic effects of IFN-γ is a major determinant of CD4+ CAR T-cell antitumor activity

Cited by 45 publications

References 71 publications

IGFBP3 induces PD-L1 expression to promote glioblastoma immune evasion

IGFBP3 induces PD-L1 expression to promote glioblastoma immune evasion

HLA-class II restricted TCR targeting human papillomavirus type 18 E7 induces solid tumor remission in mice

A Mendelian analysis of the relationships between immune cells and breast cancer

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