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The Critical Role of CD103+ Dendritic Cells in Anti-Tumor T Cell Immunity

  • Author(s): Broz, Miranda Leslie
  • Advisor(s): Krummel, Matthew F
  • et al.
Abstract

It is well understood that antigen-presenting cells (APC) within tumors typically do not maintain cytotoxic T cell (CTL) function, despite engaging them. Across multiple mouse tumor models and human biopsies, we have delineated the intratumoral and lymph node trafficking dendritic-cell (DC) populations as distinct from macrophage subsets. Within these, CD103+ dendritic cells (DCs) are extremely sparse and yet remarkably capable CTL stimulators. These are uniquely dependent upon Irf8, Zbtb46, and Batf3 transcription factors and generated by GM-CSF and Flt3L cytokines. Regressing tumors have higher proportions of these cells, T cell-dependent immune clearance relies upon them, and abundance of their transcripts in human tumors predict clinical outcome. Even further, this population of stimulatory CD103+ DCs is required for the trafficking of tumoral antigen to the lymph node and the generation of anti-tumor T cell responses. As tumoral load of these DCs is predictive of immunotherapeutic clinical benefit, this cell type presents many opportunities for novel prognostic, diagnostic, and therapeutic approaches across multiple cancer types.

Current cancer immunotherapies are predicated on enhancing the ability of host or introduced T cells to reject tumors. However, efficient CTL function requires frequent re-priming and abundant tumor macrophages, which capture CTL at the tumor margin, either fail to achieve this and/or actively inhibit T cell responses. Here, we show that the abundant macrophages in tumors have a functional opposite, in the form of antigen-presenting CD103+ DC. These cells efficiently cross-present tumor antigens locally and in the lymph node and are differentially distributed within the tumor microenvironment compared to tolerizing APC. We describe how intratumoral CD103+ DC are uniquely targetable, how their abundance is required for T cell therapy in mice, and how their transcript abundance predicts outcome in human cancers.

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