Abstract
In the era of immune checkpoint blockade cancer therapy, cytokines have become an attractive immune therapeutics to increase response rates. Interleukin 21 (IL21) as a single agent has been evaluated for cancer treatment with good clinical efficacy. However, the clinical application of IL21 is limited by a short half-life and concern about potential immune suppressive effect on dendritic cells. Here, we examined the antitumor function of a half-life extended IL21 alone and in combination with PD-1 blockade using preclinical mouse tumor models. We also determined the immune mechanisms of combination therapy. We found that combination therapy additively inhibited the growth of mouse tumors by increasing the effector function of type 1 lymphocytes. Combination therapy also increased the fraction of type 1 dendritic cells (DC1s) and M1 macrophages in the tumor microenvironment (TME). However, combination therapy also induced immune regulatory mechanisms, including the checkpoint molecules Tim-3, Lag-3, and CD39, as well as myeloid derived suppressor cells (MDSC). This study reveals the mechanisms of IL21/PD-1 cooperation and shed light on rational design of novel combination cancer immunotherapy.
Highlights
Immune checkpoint blockade (ICB) has showed therapeutic efficacy and greatly prolonged survival in cancer patients
T cells was significantly enhanced after combination treatment (Figures 4J,O–R). These results indicate that HSA-Interleukin 21 (IL21)/PD-1 blockade combination therapy may drive tumor-infiltrating lymphocytes (TILs) into a hyperactivated state that is controlled by multiple immune checkpoint molecules (Yang et al, 2020)
Our work demonstrates that the half-life-extended HSA-IL21 retains the antitumor effect of WT IL21 and produces superior efficacy when combined with PD-1 blockade in vivo
Summary
Immune checkpoint blockade (ICB) has showed therapeutic efficacy and greatly prolonged survival in cancer patients. ICB therapy has removed a major roadblock of cancer treatment by targeting molecules that hinder T cell-mediated immune responses (Hodi et al, 2010; Brahmer et al, 2012; Topalian et al, 2012). This new development has ushered in rich opportunities for using immune agonists as combination therapies. Cytokines drive T cell-mediated immune responses by enhancing proliferation, promoting type 1 differentiation, increasing the effector function, and directing the memory generation (Shourian et al, 2019; Zander et al, 2019; Xue et al, 2021). The cytokine-based immunotherapy is in theory in concert with ICB therapy and promises to further improve clinical response rates
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