Natural Antibodies Alert the Adaptive Immune System of the Presence of Transformed Cells in Early Tumorigenesis

Rawat, Kavita; Soucy, Shannon M.; Kolling, Fred; Diaz, Kiara Manohar; King, W. T.; Tewari, Anita; Jakubzick, Claudia

doi:10.4049/jimmunol.2200447

Cited by 11 publications

(12 citation statements)

References 32 publications

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“…Recently, additional transgenic mouse models have been employed to further clarify the role of NAbs in identifying and eliminating neoantigen-expressing tumor cells, including those found in the precancerous stage. For example, the sera obtained from naive AID-/- mice with a hyper-IgM repertoire exhibited strong binding to MB16F10 melanoma cells, while no binding was observed with sera obtained from Rag2-/- mice, who lack antibodies ( 82 ).…”

Section: The Anti-tumor Function Of B-1 Cellsmentioning

confidence: 99%

“…To support this notion, a series of studies were conducted on transgenic animals lacking a complete repertoire of NAbs. IghelMD4 mice, characterized by over 90% of IgM-secreting B cells specific to chicken egg lysozyme, exhibited a greater tumor burden compared to wild-type (WT) mice in various tumor models ( 82 – 84 ).…”

Section: The Anti-tumor Function Of B-1 Cellsmentioning

confidence: 99%

“…To demonstrate the primary role of circulating NAbs in contrast to those expressed in B cell membranes in the process of binding and eliminating tumor cells, Rawat et al. ( 82 ) established a mouse model with a deficiency in circulating NAbs. The authors developed a mouse model lacking circulating IgG and IgM antibodies while preserving membrane-bound IgM by crossbreeding hyper-IgM Aicda -/- mice with sIgM -/- mice.…”

Section: The Anti-tumor Function Of B-1 Cellsmentioning

confidence: 99%

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The role of B-1 cells in cancer progression and anti-tumor immunity

Rodríguez-Zhurbenko,

Hernández

2024

Front. Immunol.

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In recent years, in addition to the well-established role of T cells in controlling or promoting tumor growth, a new wave of research has demonstrated the active involvement of B cells in tumor immunity. B-cell subsets with distinct phenotypes and functions play various roles in tumor progression. Plasma cells and activated B cells have been linked to improved clinical outcomes in several types of cancer, whereas regulatory B cells have been associated with disease progression. However, we are only beginning to understand the role of a particular innate subset of B cells, referred to as B-1 cells, in cancer. Here, we summarize the characteristics of B-1 cells and review their ability to infiltrate tumors. We also describe the potential mechanisms through which B-1 cells suppress anti-tumor immune responses and promote tumor progression. Additionally, we highlight recent studies on the protective anti-tumor function of B-1 cells in both mouse models and humans. Understanding the functions of B-1 cells in tumor immunity could pave the way for designing more effective cancer immunotherapies.

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Section: The Anti-tumor Function Of B-1 Cellsmentioning

confidence: 99%

Section: The Anti-tumor Function Of B-1 Cellsmentioning

confidence: 99%

Section: The Anti-tumor Function Of B-1 Cellsmentioning

confidence: 99%

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The role of B-1 cells in cancer progression and anti-tumor immunity

Rodríguez-Zhurbenko,

Hernández

2024

Front. Immunol.

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“…These IgM or IgG natural antibodies can play a role in detecting neoantigens expressed by cancer cells, and they have recently been shown to play a role in tumor control. [80][81][82] In this case, IL-10 may be acting as an immunosuppressant to CD8+ T cells and activated B cells, and B reg cells may be a potential source of the IL-10.…”

Section: Cd8+ T Cells Control Tumor Outgrowth and Prolong Survival In...mentioning

confidence: 99%

Inhibiting DNA methylation and RNA editing upregulates immunogenic RNA to transform the tumor microenvironment and prolong survival in ovarian cancer

Gomez

Cox

Walker

et al. 2022

J Immunother Cancer

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BackgroundNovel therapies are urgently needed for ovarian cancer (OC), the fifth deadliest cancer in women. Preclinical work has shown that DNA methyltransferase inhibitors (DNMTis) can reverse the immunosuppressive tumor microenvironment in OC. Inhibiting DNA methyltransferases activate transcription of double-stranded (ds)RNA, including transposable elements. These dsRNAs activate sensors in the cytoplasm and trigger type I interferon (IFN) signaling, recruiting host immune cells to kill the tumor cells. Adenosine deaminase 1 (ADAR1) is induced by IFN signaling and edits mammalian dsRNA with an A-to-I nucleotide change, which is read as an A-to-G change in sequencing data. These edited dsRNAs cannot be sensed by dsRNA sensors, and thus ADAR1 inhibits the type I IFN response in a negative feedback loop. We hypothesized that decreasing ADAR1 editing would enhance the DNMTi-induced immune response.MethodsHuman OC cell lines were treated in vitro with DNMTi and then RNA-sequenced to measure RNA editing. Adar1 was stably knocked down in ID8Trp53-/-mouse OC cells. Control cells (shGFP) or shAdar1 cells were tested with mock or DNMTi treatment. Tumor-infiltrating immune cells were immunophenotyped using flow cytometry and cell culture supernatants were analyzed for secreted chemokines/cytokines. Mice were injected with syngeneic shAdar1 ID8Trp53-/-cells and treated with tetrahydrouridine/DNMTi while given anti-interferon alpha and beta receptor 1, anti-CD8, or anti-NK1.1 antibodies every 3 days.ResultsWe show that ADAR1 edits transposable elements in human OC cell lines after DNMTi treatment in vitro. Combining ADAR1 knockdown with DNMTi significantly increases pro-inflammatory cytokine/chemokine production and sensitivity to IFN-β compared with either perturbation alone. Furthermore, DNMTi treatment and Adar1 loss reduces tumor burden and prolongs survival in an immunocompetent mouse model of OC. Combining Adar1 loss and DNMTi elicited the most robust antitumor response and transformed the immune microenvironment with increased recruitment and activation of CD8+ T cells.ConclusionIn summary, we showed that the survival benefit from DNMTi plus ADAR1 inhibition is dependent on type I IFN signaling. Thus, epigenetically inducing transposable element transcription combined with inhibition of RNA editing is a novel therapeutic strategy to reverse immune evasion in OC, a disease that does not respond to current immunotherapies.

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“…In addition to T lymphocytes, other innate immune cells, including natural killer (NK) cells, NKT cells, macrophages, dendritic cells, mast cells, and neutrophils, also play an important role in controlling tumor growth 15 . As is known, tumor cells downregulated or lacked MHC class I molecules, and lacked the ability to present tumor‐related antigens, making tumor cells present a low immunogenicity phenotype and thus escape the immune surveillance of the body 16‐19 . MHC class I molecules expressed on the surface of normal cells are the main molecules to avoid killing attack of self‐NK cells 20 .…”

Section: Introductionmentioning

confidence: 99%

Immune‐check blocking combination multiple cytokines shown curative potential in mice tumor model

Geng

Cai

et al. 2023

Cancer Medicine

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Objective In order to ensure the stable transcription of target genes, we constructed a eukaryotic high expression vector carrying an immune‐check inhibitor PD‐1v and a variety of cytokines, and studied their effects on activating immune response to inhibit tumor growth. Methods A novel eukaryotic expression plasmid vector named pT7AMPCE containing T7RNA polymerase, T7 promoter, internal ribosome entry site (IRES), and poly A tailing signal was constructed by T4 DNA ligase, on which homologous recombination was used to clone and construct the vector carrying PD‐1v, IL‐2/15, IL‐12, GM‐CSF, and GFP. In vitro transfection of CT26 cells was performed, and the protein expression of PD‐1v, IL‐12 and GM‐CSF was detected by Western blot and ELISA after 48 h. Mice were subcutaneously inoculated with CT26‐IRFP tumor cells in the rib abdomen, and the tumor tissues were injected with PD‐1v, IL‐2/15, IL‐12, and GM‐CSF recombinant plasmids for treatment during the experimental period. The efficacy of the treatment was evaluated by assay tumor size and survival time of tumor‐bearing mice during the experiment. Expression levels of IFN‐γ, TNF, IL‐4, IL‐2, and IL‐5 in mouse blood were measured using the CBA method. Tumor tissues were extracted and immune cell infiltration in tumor tissues was detected by HE staining and the IHC method. Results The recombinant plasmids carrying PD‐1v, IL‐2/15, IL‐12, and GM‐CSF were successfully constructed, and the Western blot and ELISA results showed that PD‐1v, IL‐12, and GM‐CSF were expressed in the supernatant of CT26 cells 48 h after in vitro cell transfection. The combined application of PD‐1v, IL‐2/15, IL‐12, and GM‐CSF recombinant plasmids significantly inhibited tumor growth in mice, and the tumor growth rate was significantly lower than that in the blank control group and GFP plasmid control group (p < 0.05). Cytometric bead array data suggested that the combination of PD‐1v and various cytokines can effectively activate immune cells. HE and IHC analysis revealed plenty of immune cell infiltrates in the tumor tissue, and a large proportion of tumor cells showed the necrotic phenotype in the combination treatment group. Conclusion The combination of immune check blockade and multiple cytokine therapy can significantly activate the body's immune response and inhibit tumor growth.

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Natural Antibodies Alert the Adaptive Immune System of the Presence of Transformed Cells in Early Tumorigenesis

Cited by 11 publications

References 32 publications

The role of B-1 cells in cancer progression and anti-tumor immunity

The role of B-1 cells in cancer progression and anti-tumor immunity

Inhibiting DNA methylation and RNA editing upregulates immunogenic RNA to transform the tumor microenvironment and prolong survival in ovarian cancer

Immune‐check blocking combination multiple cytokines shown curative potential in mice tumor model

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