Dissecting the Tumor Myeloid Compartment Reveals Rare Activating Antigen Presenting Cells, Critical for T cell Immunity

By Miranda L. Broz, M. Binnewies, Bijan Boldajipour, Amanda E. Nelson, J. Pollock, D. Erle, A. Barczak, M. Rosenblum, A. Daud, D. Barber and 5 more. Cancer Cell, 2014

769 citations recorded by the source corpus.

SUMMARY 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 tumor biopsies, we have delineated the intratumoral dendritic-cell (DC) populations as distinct from macrophage populations. Within these, CD103+ 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 correlates with clinical outcome. This cell type presents opportunities for prognostic and therapeutic approaches across multiple cancer types.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/0650858f43fa512a3654411abb6dc31ef80a76a4

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

1. Guido Kroemer
2. L. Galluzzi
3. L. Zitvogel
4. D. Pardoll
5. Oliver Kepp
6. S. Topalian
7. A. Buqué
8. Florent Ginhoux

In Oncology

1. D. Pardoll
2. Guido Kroemer
3. L. Galluzzi
4. L. Zitvogel
5. S. Topalian
6. Janis Taube
7. Oliver Kepp
8. Zena Werb

Citations in the corpus

• Critical Role for CD103+/CD141+ Dendritic Cells Bearing CCR7 for Tumor Antigen Trafficking and Priming of T Cell Immunity in Melanoma (2016, positive): “We applied this approach to mice bearing the B78ChOVA melanoma (Broz et al., 2014), a variant of B16-F10 (Fidler, 1975) engineered to express both ovalbumin as a neo-tumor antigen as well as the fluorescent mCherry protein to track antigen uptake by phagocytes.”
• Immunogenic chemotherapy sensitizes tumors to checkpoint blockade therapy (2016, positive): “These tu- mor-infiltrating cells expressed CD103 and thus resembled DCs previously identified as critical stimulators of antitumor CD8+ T cell immunity (Broz et al., 2014; Ruffell et al., 2014; Spranger et al., 2015).”
• Immunological Effects of Conventional Chemotherapy and Targeted Anticancer Agents. (2015, background): “Lymphocytes, however, are not sufficient for the elicitation of an optimal tumor-targeting immune response, which relies on the critical contribution of a particular subset of dendritic cells (DCs) that are endowed with potent phagocytic activity, and (in mice) express CD8a as well as tumor necrosis”
• Tumor-residing Batf3 dendritic cells are required for effector T cell trafficking and adoptive T cell therapy (2017, methodology): “To investigate a direct role for Batf3-lineage CD103+ DCs in effector T cell recruitment, we generated CD11c-DTR/Batf3 / or CD11c-DTR/WT mixed bone marrow chimeras into BP-SIY host mice, as Batf3 is known to be required for development of CD103+ DCs (Broz et al., 2014; Edelson et al., 2010).”
• The Cancer Stem Cell Niche: How Essential is the Niche in Regulating Stemness of Tumor Cells? (2015, positive): “…to further break down the ECM, which in turn releases TGF-b and various growth factors like VEGF-A, to allow tumor expansion. cells (DCs), which can efficiently stimulate CD8+ T cells, is masked from tumor antigens by other tolerizing antigen-presenting myeloid cell populations (Broz et al., 2014).”
• Expansion and activation of CD103+ dendritic cell progenitors at the tumor site enhances tumor responses to therapeutic PD-L1 and BRAF inhibition (2016, positive): “934 Immunity 44, 924–938, April 19, 2016 activation of intratumoral CD8+ T effector cells is dependent on intratumoral CD103+ DCs (Broz et al., 2014), suggesting that the limited infiltration of CD8+ T cells observed in B16 and Braf-mutant lesions could be a consequence of the reduced accumulation…”
• Single cell transcriptomics of human and mouse lung cancers reveals conserved myeloid populations across individuals and species (2019, background): “Heterogeneity among dendritic cells (DCs) is also appreciated (Broz et al., 2014), but again the complete range of DC states within tumors is not fully known.”