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Background <p>While immune checkpoint inhibitors (ICIs) have failed to improve outcomes in unselected ovarian cancer populations, objective responses are observed in a minority of ovarian clear cell carcinoma (OCCC) cases, implying biological heterogeneity and a yet-undefined immunologically responsive subset within this histotype.</p> Methods <p>We performed immunohistochemical profiling of tumor-infiltrating immune cells and analyzed transcriptomic data from human OCCC cohorts. Functional studies were conducted using an immunocompetent syngeneic OCCC mouse model to assess the effects of IL-17 on tumor cell inflammatory signaling, immune microenvironment remodeling, and responsiveness to immune checkpoint blockade, including single-cell RNA sequencing of tumor-infiltrating T cells.</p> Results <p>OCCC exhibited an immune-sparse tumor microenvironment with relative enrichment of CD4⁺ T cells. <i>RORC</i> expression was elevated in OCCC but showed intertumoral heterogeneity. In the transcriptome data (<i>n</i> = 180), an <i>IL17A</i><sup>high</sup> subset (5%), enriched within the <i>RORC</i><sup>high</sup> fraction, exhibited a T cell–inflamed gene expression profile independent of microsatellite instability and tumor mutational burden, yet was not associated with survival. Mechanistically, IL-17 directly activated NF-κB–dependent inflammatory programs in OCCC tumor cells, inducing cytokines and chemokines involved in T-cell recruitment and activation. In the syngeneic model, IL-17 exposure increased intratumoral CD4⁺ and CD8⁺ T-cell infiltration and activation. Single-cell profiling further revealed expansion of Th17/Tfh-like CD4⁺ T cells and cytotoxic, non-terminally exhausted CD8⁺ T cells. Consistent with these changes, anti–PD-L1 therapy improved survival in Th17-biased partial chimera mice.</p> Conclusions <p>IL-17–responsive, tumor cell–intrinsic inflammatory programming remodels the tumor immune microenvironment toward an immunotherapy-permissive state. These findings establish IL-17–responsive tumor cell inflammatory programming as a mechanistic axis shaping immune checkpoint sensitivity and provide a rationale for biomarker-guided immunotherapy strategies.</p>

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IL-17–driven tumor cell–intrinsic inflammatory programming creates an immunotherapy-permissive microenvironment

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月30日

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  • Kosuke Murakami,
  • Shiki Takamura,
  • Chiho Miyagawa,
  • Shiro Takamatsu,
  • Yoko Kashima,
  • Koji Nagaoka,
  • Yukari Kobayashi,
  • Yoshiyuki Hakata,
  • Shigeki Kato,
  • Sachiyo Tsuji-Kawahara,
  • Ding Nan,
  • Ronald Chandler,
  • Satoru Takahashi,
  • Masaaki Miyazawa,
  • Kazuhiro Kakimi,
  • Noriomi Matsumura

摘要

Background

While immune checkpoint inhibitors (ICIs) have failed to improve outcomes in unselected ovarian cancer populations, objective responses are observed in a minority of ovarian clear cell carcinoma (OCCC) cases, implying biological heterogeneity and a yet-undefined immunologically responsive subset within this histotype.

Methods

We performed immunohistochemical profiling of tumor-infiltrating immune cells and analyzed transcriptomic data from human OCCC cohorts. Functional studies were conducted using an immunocompetent syngeneic OCCC mouse model to assess the effects of IL-17 on tumor cell inflammatory signaling, immune microenvironment remodeling, and responsiveness to immune checkpoint blockade, including single-cell RNA sequencing of tumor-infiltrating T cells.

Results

OCCC exhibited an immune-sparse tumor microenvironment with relative enrichment of CD4⁺ T cells. RORC expression was elevated in OCCC but showed intertumoral heterogeneity. In the transcriptome data (n = 180), an IL17Ahigh subset (5%), enriched within the RORChigh fraction, exhibited a T cell–inflamed gene expression profile independent of microsatellite instability and tumor mutational burden, yet was not associated with survival. Mechanistically, IL-17 directly activated NF-κB–dependent inflammatory programs in OCCC tumor cells, inducing cytokines and chemokines involved in T-cell recruitment and activation. In the syngeneic model, IL-17 exposure increased intratumoral CD4⁺ and CD8⁺ T-cell infiltration and activation. Single-cell profiling further revealed expansion of Th17/Tfh-like CD4⁺ T cells and cytotoxic, non-terminally exhausted CD8⁺ T cells. Consistent with these changes, anti–PD-L1 therapy improved survival in Th17-biased partial chimera mice.

Conclusions

IL-17–responsive, tumor cell–intrinsic inflammatory programming remodels the tumor immune microenvironment toward an immunotherapy-permissive state. These findings establish IL-17–responsive tumor cell inflammatory programming as a mechanistic axis shaping immune checkpoint sensitivity and provide a rationale for biomarker-guided immunotherapy strategies.