Antibody-mediated blockade of the IL23 receptor destabilizes intratumoral regulatory T cells and enhances immunotherapy

Abstract

Significance Regulatory T cells rely on active processes to maintain a suppressive phenotype inside a tumor, leading to increased tumor burden and worse cancer outcomes. Here, we report a pathway to interfere with regulatory T cell (Treg) stability by disrupting the expression of the interleukin 23 receptor. This approach increases Treg responsiveness to interleukin 12, leading to increased production of gamma-interferon and more efficient antitumor immune responses. The combined engagement of independent pathways to destabilize Treg through the interleukin 23 receptor and the glucocorticoid-induced TNFR-related protein receptor has a synergistic impact on the Treg phenotype and promotes antitumor immune responses. These findings expand our understanding of regulatory T-cell biology and offer tools for cancer immunotherapy.

Revisiting Coley’s Toxins: Immunogenic Cardiolipins from Streptococcus pyogenes

“…TLR2 typically responds to lipid-containing immunogens, while TLR4 typically responds to carbohydrate-derived immunogens. This is further supported by previous reports that TLR2 can respond to cardiolipin self-immunogens released by damaged mitochondria. , …”

“…This is further supported by previous reports that TLR2 can respond to cardiolipin selfimmunogens released by damaged mitochondria. 20,21 Signaling through the TLR2 receptor typically requires a heterodimer of TLR2−TLR6 or TLR2−TLR1. 22−25 We used CRISPR/C as knockdowns in human monocytes to distinguish these possibilities (Figure 4).…”

CD8+ T cell-intrinsic IL-6 signaling promotes resistance to anti-PD-L1 immunotherapy

“…Direct inhibition of CTLs by IL-6 is mechanistically distinct from other cytokine-dependent processes that can potentially inhibit ICI efficacy, including recruitment of inhibitory myeloid cells by VEGF, 56 IL-1β, 57 IL-8, 58 , 59 or LIF, 60 suppression of tumor CTL infiltration by TGFβ, 61 and support of Treg function by IL-23. 62 , 63 Importantly, therapies targeting IL-6 and IL6R are approved for several conditions including rheumatoid arthritis, cytokine release syndrome, giant cell arteritis, and multicentric Castleman disease. 64 Given the extensive clinical experience with IL-6 inhibitors, and the pressing need to improve upon existing immunotherapies, combination of ICIs with approved anti-IL-6/IL6R agents warrants investigation in cancer patients.…”

IL-23 stabilizes an effector Treg cell program in the tumor microenvironment

“…Thus far, identifying IL-23R-expressing cells has been challenging due to the poor specificity of available antibodies and low expression of IL-23R. Nevertheless, two reports have suggested that T reg cells express IL-23R in preclinical models of cancer 14 , 22 . By generating an IL-23R reporter mouse, we demonstrated IL-23R expression in T reg cells in the TME.…”