Scholarlink

Background <p>Tumor-associated macrophages (TAMs) are key drivers of immunosuppressive inflammation in the breast cancer microenvironment, promoting tumor progression and resistance to immune checkpoint blockade. Our previous work identified extracellular IFI16/IFI202 as tumor-derived damage-associated molecular patterns which activate pro-inflammatory signaling in TAMs via Toll-like receptor 2, thereby facilitating immune evasion. In this study, we investigated the therapeutic potential of a monoclonal antibody (mAb) targeting extracellular IFI202 to suppress tumor-promoting inflammation and to restore antitumor immunity.</p> Methods <p>We developed a mAb against IFI202 and evaluated its functions in bone marrow-derived macrophages (BMDMs) using ELISA and western blotting. In vivo efficacy was assessed in the mouse mammary tumor virus-polyoma virus middle T-antigen breast cancer model by treating with IFI202 mAb, or anti–programmed death-1 (PD-1) antibody, as monotherapies or in combination. Tumor volume, metastasis, cytokine levels, and immune cell infiltration were analyzed. Statistical significance was assessed using Mann–Whitney U test or ANOVA, with <i>P</i> &lt; 0.05 considered significant.</p> Results <p>Conditioned medium obtained from 4T1 breast cancer cells pre-incubated with IFI202 mAb suppressed secretion of IL-6 and TNF-α, and inhibited activation of ERK and NF-κB in BMDMs. Intraperitoneal injection of IFI202 mAb in mouse mammary tumor virus-polyoma middle T-antigen mice significantly reduced tumor growth and lung metastasis. In addition, IL-1β expression, CD8<sup>+</sup> T cell infiltration, and levels of granzyme B and interferon-γ, were enhanced in the tumors of IFI202 mAb-treated mice, indicating that IFI202 mAb restored cytotoxic function of CD8<sup>+</sup> T-cells. Combination of IFI202 mAb with PD-1 mAb significantly improved antitumor efficacy compared to monotherapy.</p> Conclusions <p>Neutralization of extracellular IFI202 suppresses TAM-mediated inflammation and supports a tumor microenvironment favorable for T-cell–mediated immunity. In combination with anti–PD-1 therapy, IFI202 mAb further enhances antitumor responses, suggesting a promising and tumor-selective strategy that may help overcome resistance to immune checkpoint blockade in breast cancer.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

IFI16/IFI202 blockade suppresses tumor growth through CD8+ T-cell–mediated immunity

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年1月3日

查看全文
  • Ga Young Lim,
  • Na-Lee Ka,
  • Seung-Su Kim,
  • Mi-Ock Lee

摘要

Background

Tumor-associated macrophages (TAMs) are key drivers of immunosuppressive inflammation in the breast cancer microenvironment, promoting tumor progression and resistance to immune checkpoint blockade. Our previous work identified extracellular IFI16/IFI202 as tumor-derived damage-associated molecular patterns which activate pro-inflammatory signaling in TAMs via Toll-like receptor 2, thereby facilitating immune evasion. In this study, we investigated the therapeutic potential of a monoclonal antibody (mAb) targeting extracellular IFI202 to suppress tumor-promoting inflammation and to restore antitumor immunity.

Methods

We developed a mAb against IFI202 and evaluated its functions in bone marrow-derived macrophages (BMDMs) using ELISA and western blotting. In vivo efficacy was assessed in the mouse mammary tumor virus-polyoma virus middle T-antigen breast cancer model by treating with IFI202 mAb, or anti–programmed death-1 (PD-1) antibody, as monotherapies or in combination. Tumor volume, metastasis, cytokine levels, and immune cell infiltration were analyzed. Statistical significance was assessed using Mann–Whitney U test or ANOVA, with P < 0.05 considered significant.

Results

Conditioned medium obtained from 4T1 breast cancer cells pre-incubated with IFI202 mAb suppressed secretion of IL-6 and TNF-α, and inhibited activation of ERK and NF-κB in BMDMs. Intraperitoneal injection of IFI202 mAb in mouse mammary tumor virus-polyoma middle T-antigen mice significantly reduced tumor growth and lung metastasis. In addition, IL-1β expression, CD8+ T cell infiltration, and levels of granzyme B and interferon-γ, were enhanced in the tumors of IFI202 mAb-treated mice, indicating that IFI202 mAb restored cytotoxic function of CD8+ T-cells. Combination of IFI202 mAb with PD-1 mAb significantly improved antitumor efficacy compared to monotherapy.

Conclusions

Neutralization of extracellular IFI202 suppresses TAM-mediated inflammation and supports a tumor microenvironment favorable for T-cell–mediated immunity. In combination with anti–PD-1 therapy, IFI202 mAb further enhances antitumor responses, suggesting a promising and tumor-selective strategy that may help overcome resistance to immune checkpoint blockade in breast cancer.