Cancer cells induce interleukin-22 production from memory CD4⁺T cells via interleukin-1 to promote tumor growth

Abstract

IL-22 has been identified as a cancer-promoting cytokine that is secreted by infiltrating immune cells in several cancer models. We hypothesized that IL-22 regulation would occur at the interface between cancer cells and immune cells. Breast and lung cancer cells of murine and human origin induced IL-22 production from memory CD4 T cells. In the present study, we found that IL-22 production in humans is dependent on activation of the NLRP3 inflammasome with the subsequent release of IL-1β from both myeloid and T cells. IL-1 receptor signaling via the transcription factors AhR and RORγt in T cells was necessary and sufficient for IL-22 production. In these settings, IL-1 induced IL-22 production from a mixed T helper cell population comprised of Th1, Th17, and Th22 cells, which was abrogated by the addition of anakinra. We confirmed these findings in vitro and in vivo in two murine tumor models, in primary human breast and lung cancer cells, and in deposited expression data. Relevant to ongoing clinical trials in breast cancer, we demonstrate here that the IL-1 receptor antagonist anakinra abrogates IL-22 production and reduces tumor growth in a murine breast cancer model. Thus, we describe here a previously unrecognized mechanism by which cancer cells induce IL-22 production from memory CD4 T cells via activation of the NLRP3 inflammasome and the release of IL-1β to promote tumor growth. These findings may provide the basis for therapeutic interventions that affect IL-22 production by targeting IL-1 activity.

IL22 drives cutaneous melanoma cell proliferation, migration and invasion through activation of miR-181/STAT3/AKT axis

“…Patients and samples CM tissues, adjacent normal tissues and peripheral blood were collected from 30 patients diagnosed with CM according to clinical and histological manifestation in department of dermatology, the Affiliated Hospital of Southwest Medical University (Based on the expression of interleukin 22 in normal human tissues and other tumor tissues obtained from published report 18,19 , we statistical estimated sample size in our study, and found that 30 cases enrolled in both patient group and health group could meet the statistical requirement.). They are 40-60 years old with 17 male and 13 female.…”

On the mechanism of anti-CD39 immune checkpoint therapy

“…34 IL-1 signaling has also been associated with increased chemoresistance in mouse models of cancer 35 and production of protumorigenic IL-22. 36 In prognostic studies, higher tumor IL-1β levels have been associated with improved survival of patients with lymph node-positive breast cancer, 37 while the use of a blocking anti-IL-1β antibody in patients with cardiovascular diseases showed a reduction on lung cancer incidence. 38 Extracellular ATP activates NLRP3 inflammasome through P2×7 receptors.…”

Can we use interleukin-1β blockade for lung cancer treatment?

“…We were able to validate the presence of IL-22 in lavages of lung cancer patients and other pulmonary diseases (16). Along these lines, murine breast cancer cells showed a reduction in tumor growth accompanied by a decreased IL-22 expression after administration of IL-1 blocking agents (9), illustrating the close connection between these two cytokines, each representing a different cytokine family. Nevertheless, the role of IL-22 on the progression of lung cancer remains elusive and will need to be further investigated.…”

“…Moreover, recent studies have demonstrated the importance of IL-1 signaling for sustaining the immunosuppressive capacities of TAM (14). In the Pointing to another mechanism, we could recently show the involvement of IL-1-dependent up-regulation of interleukin-22 expression (IL-22) in murine and human breast and lung cancer models (9). IL-22 is, among other important functions, involved in tissue repair mechanisms and induces signal transducer and activator of transcription-3-dependent (STAT3) proliferative signaling cascades (15).…”

“…More specifically, interleukin-1 is involved in the development, progression and invasiveness of chemically induced murine fibrosarcomas (7) and the development of asbestosisinduced mesothelioma (8). Blockade of IL-1 has been shown to be able to slow tumor progression in mice and men (9,10).…”