{
  "abstract": "Background Ovarian cancer is the sixth-leading cause of cancer-related death in women in the United States. 1 While immune checkpoint blockade (ICB) therapy has shown remarkable efficacy in other cancers,2 ICB has failed to be effective in ovarian cancer.3 In this study, we sought to uncover mechanisms contributing to the dysfunctional, ICB-resistant T cell responses observed in ovarian cancer.Methods To study T cell responses in ovarian cancer, we implanted syngeneic ovarian cancer cells driven by Ccne1 OE p53R172H Akt2OE and KrasG12V (CPAK)4 intraperitoneally in C57BL/6J mice. CPAK cells were engineered to express the model antigen SIY. Immune cells were profiled using RNA sequencing, flow cytometry, and immunofluorescence staining. Immunological mechanism was dissected using adoptive T cell transfers and ex vivo co-cultures.Results CPAK-SIY tumors are resistant to ICB therapy, despite intratumoral infiltration of CD8 + T cells. Analysis of adoptively transferred naïve tumor-specific T cells illustrated robust T cell proliferation and activation in tumor-draining lymph nodes, indicating that the dysfunctional immune response was not caused by poor priming, but rather due to a suppressive tumor microenvironment. Single-cell RNA sequencing analysis of intratumoral dendritic cells (DCs) revealed a CD103+ CD11b+ DC population that is derived from type-2-conventional DCs (cDC2s) and is similar to a suppressive subset found in the gut at steady state.5 6 Although gut-resident CD103+ CD11b+ DCs suppress immune responses via regulatory T cells (Tregs), depleting Tregs from CPAK-SIY tumor-bearing mice did not improve intratumoral tumor-specific T cell responses, indicating that tumor-resident CD103+ CD11b+ DCs suppress immune responses through a non-Treg-mediated mechanism. Chemokine and cytokine analysis demonstrated that tumor-resident CD103+ CD11b+ DCs and type-1-conventional DCs (cDC1s) could recruit CD8+ T cells equally well through the CXCL16-CXCR6 axis; however, cDC1s produced significantly more IL-12 compared to CD103+ CD11b+ DCs. Furthermore, in ex vivo co-culture assays, only cDC1s could induce robust T cell stimulation. Consequently, mouse models lacking cDC2s and cDC2-derived CD103+ CD11b+ DCs displayed enhanced CPAK-SIY immune responses, characterized by increased tumor infiltration of activated CD8+ T cells and significantly longer survival. The enhanced T cell response was associated with stimulatory cytokine production by cDC1s, as treating wildtype CPAK-SIY tumor-bearing mice with half-life extended IL-12 also resulted in increased tumor infiltration of activated CD8+ T cells and significantly decreased tumor burden.Conclusions Our work suggests that intratumoral CD103 + CD11b+ DCs suppress anti-tumor immune responses. Furthermore, these results provide additional evidence for the growing appreciation that DC subsets beyond the stimulatory cDC1 subset directly impact anti-tumor immune responses.Acknowledgements We thank the Koch Institute’s Swanson Biotechnology Core Facility and MIT BioMicro Center for technical support. This work was supported by Break Through Cancer, the Margaret A. Cunningham Immune Mechanisms in Cancer Research Fellowship, the MIT School of Science Fellowship in Cancer Research, and the Ludwig Center at MIT Fellowship.References Siegel RL, Kratzer TB, Giaquinto AN, Sung H, Jemal A. Cancer statistics, 2025. CA A Cancer J Clinicians 2025;75:10–45.Ribas A, Wolchok JD. Cancer immunotherapy using checkpoint blockade. Science 2018;59:1350–1355.Kandalaft LE, Odunsi K, Coukos G. Immunotherapy in ovarian cancer: are we there yet? JCO 2019;37:2460–2471.Iyer S, et al. Genetically defined syngeneic mouse models of ovarian cancer as tools for the discovery of combination immunotherapy. Cancer Discovery 2021;11:384–407.Coombes JL, et al. A functionally specialized population of mucosal CD103+ DCs induces Foxp3+ regulatory T cells via a TGF-β– and retinoic acid-dependent mechanism. Journal of Experimental Medicine 2007;204:1757–1764.Bain CC, et al. TGFβR signalling controls CD103+CD11b+ dendritic cell development in the intestine. Nat Commun 2017;8:620.Ethics Approval All mouse experiments were approved by MIT’s Committee on Animal Care (CAC) – PHS Animal Welfare Assurance # D16-00078 (A3125-01).",
  "authors": [
    {
      "affiliations": [
        "Massachusetts Institute of Technology, Cambridge, MA, USA"
      ],
      "name": "Fiona Chatterjee"
    },
    {
      "affiliations": [
        "Massachusetts Institute of Technology, Cambridge, MA, USA"
      ],
      "name": "Vincent Butty"
    },
    {
      "affiliations": [
        "Harvard Medical School, Boston, MA, USA"
      ],
      "name": "Jia-Yun Chen"
    },
    {
      "affiliations": [
        "Massachusetts Institute of Technology, Cambridge, MA, USA"
      ],
      "name": "Lauren Duhamel"
    },
    {
      "affiliations": [
        "Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA"
      ],
      "name": "K Dane Wittrup"
    },
    {
      "affiliations": [
        "Ludwig Center for Cancer Research at Harvard, Harvard Medical School, Boston, MA, USA"
      ],
      "name": "Sandro Santagata"
    },
    {
      "affiliations": [
        "Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA, USA"
      ],
      "name": "Stefani Spranger"
    }
  ],
  "title": "765 Imbalance between suppressive CD103+ CD11b+dendritic cells and type 1 conventional dendritic cells blunts anti-tumor T cell responses in ovarian cancer",
  "uid": "e433af7d-1a72-5e54-8884-3ebee757a282"
}