Immunotherapy for lung cancer combining the oligodeoxynucleotides of TLR9 agonist and TGF-β2 inhibitor

Yao, Yunpeng; Li, Jianhua; Qu, Kuo; Wang, Yangeng; Wang, Zhe; Lu, Weiyue; Yu, Yongli; Wang, Liying

doi:10.1007/s00262-022-03315-0

Cited by 8 publications

(15 citation statements)

References 77 publications

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“…So, we determined whether TIO3 could activate TLR9 signals. In our previous study (27), there were no changes of TLR9 expression between the TIO3 and PBS groups. Moreover, the TIO3 didn't affect the mRNA expression of the expression of downstream molecules of TLR9 signals, such as the IRF5, TNF-a an IFN-a.…”

Section: Discussionmentioning

confidence: 70%

“…In this study, we demonstrated that TIO3 also broadly inhibits sTGF-b2 expression in tumor cell lines and glioma tissues, as well as in antitumor effector CD4 + and CD8 + T cells. TIO3 has also been confirmed capable of entering lung tumor tissues and tumor cells in vitro and in vivo (27). Our previous study revealed that the percentages of Cy3 + cells reached 100% of the cultured LLC cells at 24 h after Cy3-TIO3 addition, and 50% of tumor tissue cells from tumor-bearing mice at 24 h post i.p.…”

Section: Discussionmentioning

confidence: 91%

“…Particularly, the preventive strategy of TCL+TIO3 in tumor immunotherapy induced a strong tumor-specific immunologic memory. In fact, the preventive tumor immunotherapy at early stage of tumor development or for preventing tumor recurrence could induce the formation of a tumor microenvironment (TME), which is conducive to the DC activation as well as the recruitment and activation of the effector immune cells, particularly CD8 + T cells and NK cells (27). Therefore, it has great potential application value for immunizing patients with TIO3 formulated with autologous TCL derived from excised glioma tissues, with the expectation of preventing the recurrence of glioma after surgery.…”

Section: Discussionmentioning

confidence: 99%

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Incorporation of a TGF-β2-inhibiting oligodeoxynucleotide molecular adjuvant into a tumor cell lysate vaccine to enhance antiglioma immunity in mice

Wang

Yang

et al. 2023

Front. Immunol.

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IntroductionTransforming growth factor β2 (TGF-β2), also known as glioma-derived T-cell suppressor factor, is associated with the impairment of tumor immune surveillance. Therefore, blocking TGF-β2 signaling probably be a feasible strategy to develop a novel type of adjuvant for glioma vaccines to enhance antitumor immunity.MethodsA TGF-β2 inhibitory oligodeoxynucleotide, TIO3, was designed with sequences complementary to the 3' untranslated region of TGF-β2 mRNA. The expression of TGF-β2 and MHC-I was detected by qPCR, western and flow cytometry in vitro. All the percentage and activation of immune cells were detected by flow cytometry. Subsequently, TIO3 was formulated with Glioma cell lysate (TCL) and investigated for its antitumor effects in GL261 murine glioma prophylactic and therapeutic models.ResultsTIO3 could efficiently downregulate the expression of TGF-β2 while increase the MHC-I's expression in GL261 and U251 glioma cells in vitro. Meanwhile, TIO3 was detected in mice CD4+ T, CD8+ T, B and Ly6G+ cells from lymph nodes after 24 hours incubation. Moreover, TCL+TIO3 vaccination significantly prolonged the survival of primary glioma-bearing mice and protected these mice from glioma re-challenge in vivo. Mechanistically, TCL+TIO3 formulation strongly evoke the antitumor immune responses. 1) TCL+TIO3 significantly increased the composition of CD4+ and CD8+ T cells from draining lymph nodes while promoted their IFN-γ production and reduced the expression of TGF-β2 and PD1. 2) TCL+TIO3 activated the NK cells with the elevation of CD69 or NKG2D expression and PD1 reduction. 3) TCL+TIO3 increased the glioma-specific lysis CTLs from spleen. 4) TCL+TIO3 downregulated PD-L1 expression in glioma tissues and in Ly6G+ cells among glioma-infiltrating immune cells.ConclusionTIO3 is a promising adjuvant for enhancing TCL-based vaccines to produce a more vigorous and long-lasting antitumor response by interfering with TGF-β2 expression.

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Section: Discussionmentioning

confidence: 70%

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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Incorporation of a TGF-β2-inhibiting oligodeoxynucleotide molecular adjuvant into a tumor cell lysate vaccine to enhance antiglioma immunity in mice

Wang

Yang

et al. 2023

Front. Immunol.

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“…The effect of this immunotherapy is depended on the activation of TLR9 because CCT repeat sequence (CCT) ODN, as a TLR9 inhibitory ODN, had no such effect. 41 However, with the deepening of the research, we found that, in the early stage of transplant tumor occurrence, the first immune cells to reach the tumor site were neutrophils, and the application of CpG ODN could also significantly increase the proportion and activation of neutrophils in tumor nodules, and the earlier the application, the stronger the inhibitory effect on tumor growth. 9 This finding aroused our great interest, so we began to pay attention to the relationship between neutrophils and tumor development.…”

Section: Introductionmentioning

confidence: 93%

The trogocytosis of neutrophils on initial transplanted tumor in mice

Zhu,

Wang,

et al. 2024

iScience

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“…The combination treatment not only significantly slowed the progression of the cancer in the mice but also increased their chances of surviving the disease. It also shielded the tumor-free animals against a subsequent attack by the cancer [155]. OT-101 (trabedersen) is an 18-mer phosphorothioate antisense oligodeoxynucleotide designed to specifically target the human TGFβ2 mRNA.…”

Section: Antisense Oligonucleotidesmentioning

confidence: 99%

Mechanism of TGFβ in Bone Metastases and its Potential Therapeutic Uses

2023

J Orthop Res Ther

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Complications associated with advanced cancer pose a clinical challenge, particularly when bone metastases are involved, as they can worsen the prognosis and reduce the patient's chances of survival. Solid tumors, such as those originating from the breast, prostate, and lungs, can potentially metastasize to bone. Mineralized bone matrices contain potent growth factors and cytokines. The bone microenvironment is distinctive, furnishing prolific soil for cancer cell proliferation. Following tumor-induced bone destruction by osteoclast, the Transforming Growth Factor (TGFβ) is released from the mineralized bone matrix. It is one of the most abundant growth factors released from the bone matrix. TGFβ stimulates tumor cell secretion of factors that accelerate bone resorption and stimulate tumor cell colonization.Consequently, TGFβ is essential for fueling cancer's vicious cycle of cancer growth and bone destruction. In addition, TGFβ promotes Epithelial-Mesenchymal Transition (EMT), increasing cell invasiveness, angiogenesis, and metastasis progression. Emerging evidence demonstrates that TGFβ inhibits immune responses, allowing opportunistic cancer cells to evade immune checkpoints and promote bone metastasis. By inhibiting TGFβ signaling pathways, cancer progression in the bone could be broken, EMT could be reversed, and immune response could be improved. However, the dual function of TGFβ as both a tumor suppressor and an enhancer pose a formidable obstacle to developing therapeutics that target TGFβ signaling. This review delves into the significance of TGFβ in the advancement of cancer and bone metastases, in addition to examining the current therapeutic prospects of TGFβ pathway targeting.

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Immunotherapy for lung cancer combining the oligodeoxynucleotides of TLR9 agonist and TGF-β2 inhibitor

Cited by 8 publications

References 77 publications

Incorporation of a TGF-β2-inhibiting oligodeoxynucleotide molecular adjuvant into a tumor cell lysate vaccine to enhance antiglioma immunity in mice

Incorporation of a TGF-β2-inhibiting oligodeoxynucleotide molecular adjuvant into a tumor cell lysate vaccine to enhance antiglioma immunity in mice

The trogocytosis of neutrophils on initial transplanted tumor in mice

Mechanism of TGFβ in Bone Metastases and its Potential Therapeutic Uses

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