Abstract
The immunoglobulin-like domain containing receptor 2 (ILDR2), a type I transmembrane protein belonging to the B7 family of immunomodulatory receptors, has been described to induce an immunosuppressive effect on T-cell responses. Besides its expression in several nonlymphoid tissue types, we found that ILDR2 was also expressed in fibroblastic reticular cells (FRC) in the stromal part of the lymph node. These immunoregulatory cells were located in the T-cell zone and were essential for the recruitment of naïve T cells and activated dendritic cells to the lymph nodes. Previously, it has been shown that an ILDR2-Fc fusion protein exhibits immunomodulatory effects in several models of autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis, and type I diabetes. Herein, we report the generation and characterization of a human/mouse/monkey cross-reactive anti-ILDR2 hIgG2 antibody, BAY 1905254, developed to block the immunosuppressive activity of ILDR2 for cancer immunotherapy. BAY 1905254 was shown to promote T-cell activation in vitro and enhance antigen-specific T-cell proliferation and cytotoxicity in vivo in mice. BAY 1905254 also showed potent efficacy in various syngeneic mouse cancer models, and the efficacy was found to correlate with increasing mutational load in the cancer models used. Additive or even synergistic antitumor effects were observed when BAY 1905254 was administered in combination with anti-PD-L1, an immunogenic cell death-inducing chemotherapeutic, or with tumor antigen immunization. Taken together, our data showed that BAY 1905254 is a potential drug candidate for cancer immunotherapy, supporting its further evaluation.
Highlights
Immune checkpoint inhibitors (ICI) have become an indispensable approach in cancer therapy
We showed that immunoglobulin-like domain containing receptor 2 (ILDR2) is expressed in a stromal cell subset in the lymph nodes, where it could affect the process of T-cell priming
We showed that an ILDR2-Fc fusion protein bind to activated, but not na€ve, human T cells
Summary
Immune checkpoint inhibitors (ICI) have become an indispensable approach in cancer therapy. Immune checkpoints, expressed by various cell subsets in the tumor microenvironment (TME) and in lymphoid organs, that is, by immune, tumor, or stromal cells [1], play a role in regulating the immune system. Immune checkpoints can be exploited by cancer cells, which can thereby shut down the antitumor immune response [2]. The PD-1/PD-L1 axis, being one of the first identified immune checkpoints, has been intensively investigated. Its blockade shows significant clinical activity and benefit in the treatment of various cancer types [3]. There is a distinct number of patients who either do not respond to PD-1/PD-L1 inhibitors or develop acquired resistance during treatment [4].
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