Immune checkpoint blockade reveals the stimulatory capacity of tumor-associated CD103⁺ dendritic cells in late-stage ovarian cancer

Abstract

Although immune infiltrates in ovarian cancer are associated with improved survival, the ovarian tumor environment has been characterized as immunosuppressive, due in part to functional shifts among dendritic cells with disease progression. We hypothesized that flux in dendritic cell subpopulations with cancer progression were responsible for observed differences in antitumor immune responses in early and late-stage disease. Here we identify three dendritic cell subsets with disparate functions in the ovarian tumor environment. CD11c+CD11b(-)CD103(+) dendritic cells are absent in the peritoneal cavity of healthy mice but comprise up to 40% of dendritic cells in tumor-bearing mice and retain T cell stimulatory capacity in advanced disease. Among CD11c+CD11b+ cells, Lair-1 expression distinguishes stimulatory and immunoregulatory DC subsets, which are also enriched in the tumor environment. Notably, PD-L1 is expressed by Lair-1(hi) immunoregulatory dendritic cells, and may contribute to local tumor antigen-specific T cell dysfunction. Using an adoptive transfer model, we find that PD-1 blockade enables tumor-associated CD103(+) dendritic cells to promote disease clearance. These data demonstrate that antitumor immune capacity is maintained among local dendritic cell subpopulations in the tumor environment with cancer progression. Similar dendritic cell subsets are present in malignant ascites from women with ovarian cancer, supporting the translational relevance of these results.

Recent advances in understanding dendritic cell development, classification, and phenotype

“…Flies et al . observed that CD11c + CD11b − CD103 + cDC1s were absent in the peritoneal cavity of healthy mice but comprise up to 40% of DCs in ovarian tumor-bearing mice and retained T-cell stimulatory capacity in advanced disease 42 . Monocytes exposed to the appropriate conditions such as treatment with the immunostimulatory agents monosodium urate crystals and Mycobacterium smegmatis can become Mo-DCs and powerful activators of tumor-specific CD8 + T cells and anti-tumor immunity 43 , 44 .…”

“…Among CD11c + CD11b + cDC2s, Lair-1 expression further distinguishes stimulatory and immunoregulatory DC subsets, which are also enriched in TME. Interestingly, programmed death-ligand 1 (PD-L1) is expressed by Lair-1( hi ) immunoregulatory DCs and may contribute to local tumor antigen-specific T-cell dysfunction 42 . Like Mo-DCs, cDC2s were found to suppress cytotoxic T lymphocyte (CTL) function in tumor-bearing mice via L-arginine metabolism, among other potential modes of action 45 , which is consistent with a previous finding that increased breakdown of the amino acids arginine and tryptophan in tumor-associated DCs negatively impacts T-cell effector function 46 .…”

Ovarian Tumor Microenvironment Signaling: Convergence on the Rac1 GTPase

“…In addition, integrin engagement and focal adhesion kinase activation recruits Rac1 to regulate spreading and adhesion on the extracellular matrix [ 26 , 89 , 108 ]. Immune cells are an integral part of the ovarian cancer TME and perform immune suppressive and activating functions that are pivotal in disease pathology [ 109 , 110 ] and these cells serve as important therapeutic targets [ 111 , 112 ]. The best-studied example of immune cell coupling to Rac1 activation in ovarian cancer is through cytokine activation of CXCR4 as detailed in Section 4.2 and Section 6 .…”

Phagocyte—extracellular matrix crosstalk empowers tumor development and dissemination

“…A recent study demonstrated a direct link between SPARC-governed collagenous matrix remodeling, LAIR-1 neutrophil engagement and the restraining of NET extrusion [173]. Notably, an immune-suppressive phenotype has also been attributed to LAIR-1 and PD-L1 highly expressed on tumor-associated dendritic cell population in late stage ovarian cancer [174]. Furthermore, cross-linking of LAIR-1 has been linked with suppression of cytotoxic T-cell activity [175].…”