An Immunosuppressive Dendritic Cell Subset Accumulates at Secondary Sites and Promotes Metastasis in Pancreatic Cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) after complete surgical resection is often followed by distant metastatic relapse for reasons that remain unclear. In this study, we investigated how the immune response at secondary sites affects tumor spread in murine models of metastatic PDAC. Early metastases were associated with dense networks of CD11b+CD11c+MHC-II+CD24+CD64lowF4/80low dendritic cells (DC), which developed from monocytes in response to tumor-released GM-CSF. These cells uniquely expressed MGL2 and PD-L2 in the metastatic microenvironment and preferentially induced the expansion of T regulatory cells (Treg) in vitro and in vivo. Targeted depletion of this DC population in Mgl2DTR hosts activated cytotoxic lymphocytes, reduced Treg, and inhibited metastasis development. Moreover, blocking PD-L2 selectively activated CD8 T cells at secondary sites and suppressed metastasis, suggesting that the DC use this particular pathway to inhibit CD8 T cell-mediated tumor immunity. Phenotypically similar DC accumulated at primary and secondary sites in other models and in human PDAC. These studies suggest that a discrete DC subset both expands Treg and suppresses CD8 T cells to establish an immunosuppressive microenvironment conducive to metastasis formation. Therapeutic strategies to block the accumulation and immunosuppressive activity of such cells may help prevent PDAC progression and metastatic relapse after surgical resection.

Kras and Tumor Immunity: Friend or Foe?

“…Importantly, GM-CSF production by Kras G12D -expressing pancreatic tumor cells promoted the recruitment of MDSCs to the tumor microenvironment, which in turn fostered tumor growth by suppressing immune clearance by CD8 + T cells (Bayne et al 2012;Pylayeva-Gupta et al 2012). Other groups have similarly found that PDAC cell lines secrete GM-CSF, resulting in MDSC differentiation and the inhibition of T-cell proliferation (Takeuchi et al 2015;Kenkel et al 2017). Kenkel and colleagues found that pancreatic tumor-cell-secreted GM-CSF induced DC differentiation and Treg-cell expansion at early sites of metastasis in KPC mice.…”

High‐affinity PD‐1 molecules deliver improved interaction with PD‐L1 and PD‐L2

“…Normally PD-L2 is mainly expressed on APC, indicating its vital role during T-cell priming, 19 whereas the signaling pathway may be exploited by tumor cells to enhance the immunosuppressive mechanism in the tumor environment. 38,39 Increasing evidence also demonstrates that PD-L2 can be expressed on many tumor cell types, 40 The therapeutic essence of anti-PD Abs as the immune-checkpoint blockade is dependent on 2 features of the binding affinity and the location of the epitope for preventing the PD-1/PD-L1 interaction. [44][45][46] For soluble PD-1 based immune-checkpoint blockade reagent, the "epitope" location is perfect for preventing the membrane PD-1 and PD-L1…”

Role of Tumor-Mediated Dendritic Cell Tolerization in Immune Evasion

“…More recently, in an orthotopic model of pancreatic cancer that metastasizes to the liver, Kenkel et al described an immunosuppressive subset of hepatic MGL2 + PD-L2 + CD11b + F4/80 − DCs that accumulate in metastatic loci. These DCs promoted Treg development in vivo and in vitro, and the development of metastasis was hindered by anti-PD-L2 or MGL2 + cell depletion (5). In an ovarian cancer model, tumor-driven Satb1 overexpression in terminally differentiated DCs results in a tolerant, pro-inflammatory state as evidenced by the secretion of Galectin-1 and IL-6, promoting tumor growth and immune evasion (30).…”

“…Given their critical role in orchestrating tumor-targeted immune responses, cancers facilitate their escape from immune recognition and subsequent progression by subverting the functions of antigen presenting cells (APCs) known as dendritic cells (DCs). This process of DC tolerization involves the genetic reprogramming of DCs to ultimately disable immune recognition of developing malignancies (3)(4)(5)(6). As the field of immuno-oncology has been primarily focused on directly enhancing the activation of effector T cells, the process of tumor-mediated DC tolerization is comprised of many unexplored opportunities for therapeutically enhancing anti-tumor immunity at earlier stages of the tumor immunity cycle.…”