Cancer Immunotherapy with Immunomodulatory Anti-CD137 and Anti–PD-1 Monoclonal Antibodies Requires BATF3-Dependent Dendritic Cells

Abstract

Weak and ineffective antitumor cytotoxic T lymphocyte (CTL) responses can be rescued by immunomodulatory monoclonal antibodies (mAbs) targeting PD-1 or CD137. Using Batf3-/- mice, which are defective for cross-presentation of cell-associated antigens, we show that Batf3-dependent dendritic cells (DCs) are essential for the response to therapy with anti-CD137 or anti-PD-1 mAbs. Batf3-/- mice failed to prime an endogenous CTL-mediated immune response toward tumor-associated antigens, including neoantigens. As a result, the immunomodulatory mAbs could not amplify any therapeutically functional immune response in these mice. Moreover, administration of systemic sFlt3L and local poly-ICLC enhanced DC-mediated cross-priming and synergized with anti-CD137- and anti-PD-1-mediated immunostimulation in tumor therapy against B16-OVA-derived melanomas, whereas this function was lost in Batf3-/- mice. These experiments show that cross-priming of tumor antigens by Flt3L- and Batf3-dependent DCs is crucial to the efficacy of immunostimulatory mAbs and represents a very attractive point of intervention to enhance their clinical antitumor effects.

IL-15 Trans-Signaling with the Superagonist RLI Promotes Effector/Memory CD8+ T Cell Responses and Enhances Antitumor Activity of PD-1 Antagonists

“…We took advantage of two well-known immunogenic solid tumor models in mice, CT26 and MC38. These tumors are controlled by CD8 + T cells thus prone to respond to immunotherapy (14,17,22,23). Moreover, studies in mice have shown a link between mutational load of the tumor and clinical efficacy of immunotherapy (24).…”

“…Tumor models, tumor inoculation in mice, and antitumor treatments CT26 and MC38 are two immunogenic tumor models controlled by CD8 + T cells and known to respond to immune checkpoint blockers such as anti-PD-1 (14)(15)(16)(17) Mouse single cell preparation from spleen, lymph node, lung, bone marrow, and tumors Spleen and lymph nodes. Single cells were obtained after mechanical disruption, and RBCs were lysed using ACK lysing buffer (spleen).…”

Dendritic Cell–Based Immunotherapy: State of the Art and Beyond

“…In theory, this might lead to a higher response rate to immune checkpoint inhibition. Furthermore, the unique capability of DCs to cross-present antigens helps to induce an immune response to a wide variety of tumor antigens when applied in conjunction with immune checkpoint inhibitors (88). The timing of the combination may be of crucial importance for its efficacy.…”

Immune response and long-term clinical outcome in advanced melanoma patients vaccinated with tumor-mRNA-transfected dendritic cells

“…[8][9][10]57 To improve clinical efficacy, it is probably necessary to combine vaccination with checkpoint modulators or other strategies countering immunological tolerance. 6,25,52,[66][67][68][69][70][71] As a combination strategy will increase the risk of side effects, it is encouraging that our vaccine study indicated low toxicity, even after long-term follow-up. One may further note that the longterm survivors (M22 and M109) responded well to treatment with ipilimumab.…”