Constitutive Expression of CCL22 Is Mediated by T Cell-Derived GM-CSF.

CCL22 is a key mediator of leukocyte trafficking in inflammatory immune responses, allergy, and cancer. It acts by attracting regulatory T cells and Th2 cells via their receptor CCR type 4 (CCR4). Beyond its role in inflammation, CCL22 is constitutively expressed at high levels in lymphoid organs during homeostasis, where it controls immunity by recruiting regulatory T cells to dendritic cells (DCs). In this study, we aimed to identify the mechanisms responsible for constitutive CCL22 expression. We confirmed that CD11c+ DCs are the exclusive producers of CCL22 in secondary lymphatic organs during homeostasis. We show that in vitro both murine splenocytes and human PBMCs secrete CCL22 spontaneously without any further stimulation. Interestingly, isolated DCs alone, however, are unable to produce CCL22, but instead require T cell help. In vitro, only the coculture of DCs with T cells or their supernatants resulted in CCL22 secretion, and we identified T cell-derived GM-CSF as the major inducer of DC-derived CCL22 expression. In vivo, Rag1 -/- mice, which lack functional T cells, have low CCL22 levels in lymphoid organs, and this can be restored by adoptive transfer of wild-type T cells or administration of GM-CSF. Taken together, we uncover T cell-derived GM-CSF as a key inducer of the chemokine CCL22 and thus, to our knowledge, identify a novel role for this cytokine as a central regulator of immunity in lymphatic organs. This knowledge could contribute to the development of new therapeutic interventions in cancer and autoimmunity.

CCL22 Signaling in the Tumor Environment.

T cell-mediated elimination of malignant cells is one cornerstone of endogenous and therapeutically induced antitumor immunity. Tumors exploit numerous regulatory mechanisms to suppress T cell immunity. Regulatory T cells (T regs) play a crucial role in this process due to their ability to inhibit antitumoral immune responses and they are known to accumulate in various cancer entities. The chemokine CCL22, predominately produced by dendritic cells (DCs), regulates T reg migration via binding to its receptor CCR4. CCL22 controls T cell immunity, both by recruiting T regs to the tumor tissue and by promoting the formation of DC-T reg contacts in the lymph node. Here, we review the current knowledge on the role of CCL22 in cancer immunity. After revising the principal mechanisms of CCL22-induced immune suppression, we address the factors leading to CCL22 expression and ways of targeting this chemokine therapeutically. Therapeutic interventions to the CCL22-CCR4 axis may represent a promising strategy in cancer immunotherapy.

Tumor lysis syndrome induced by tebentafusp.

Tebentafusp, a bispecific T-cell receptor fusion protein directed against gp100 and CD3, can improve survival in patients with metastatic uveal melanoma and was recently approved for the treatment of HLA-A*02:01-positive uveal melanoma patients. Since tebentafusp often induces cytokine-release syndrome, doses must be escalated and patients monitored as inpatients after the first infusions. The occurrence of tumor lysis syndrome, a potentially life-threatening condition, after administration of a single dose of tebentafusp, is reported here. With adequate therapy, including the application of rasburicase, the patient made a full recovery. It is important to raise awareness of the adverse event profile of this new therapeutic approach among healthcare professionals to promptly recognize and treat side effects.

Tebentafusp is a new treatment for a type of eye cancer called uveal melanoma. It helps the body's defense system fight against cancer cells and has shown promise in helping patients live longer. However, not all patients with uveal melanoma can use this treatment. Only those who have a specific gene marker called HLA-A*02:01-positive can benefit from it. Like any new treatment, tebentafusp may have some side effects. One of them is called cytokine-release syndrome, which can cause symptoms like rash, fever and flu-like feelings. Usually, this side effect is not serious and can be treated well. There was a rare but serious case where one patient had a bad reaction after getting only one dose of tebentafusp. This reaction is called tumor lysis syndrome, which happens when cancer cells break down quickly and release harmful substances into the blood. This can be life-threatening. Thankfully, the patient received the right treatment and got better. This information is shared here with doctors and patients, so they know about possible side effects and can use tebentafusp safely.

Peritumoural CCL1 and CCL22 expressing cells in hepatocellular carcinomas shape the tumour immune infiltrate.

Development, course of disease and prognosis of hepatocellular carcinomas (HCC) are strongly influenced by the immune system. Immunosuppressive regulatory T cells (Treg) have been shown to negatively impact disease progression and survival. To further understand the mechanisms of Treg attraction to HCC lesions, this study provides an analysis of Treg attracting chemokines in human HCC tissues. We analysed the expression of the Treg attracting chemokines CCL1 and CCL22 as well as the infiltration of FoxP3+ Treg and CD8+ T cells in paraffin-embedded tissue sections of 62 HCC patients. Expression of both chemokines was detected in 47 of 62 tissue slides. Chemokine expression was generally higher in tumour stroma and peritumoural liver tissue than in the tumour tissue itself. CD8+ T cells and FoxP3+ Treg were found at high levels in many tumour tissues. Intratumoural infiltration of Treg positively correlated with CCL22 levels in peritumoural liver tissue. In contrast, no correlation of Treg numbers and expression of CCL1 was detected. In summary, we describe here that the chemokines CCL1 and CCL22 are expressed in HCC tissues and, to a higher extent, in the stroma and peritumoural liver tissue. CCL22 may contribute to Treg recruitment and immunosuppression, whereas the role of CCL1 remains to be defined. It will be interesting to investigate the potential of these chemokines as drug targets for cancer therapy.

CCL22 controls immunity by promoting regulatory T cell communication with dendritic cells in lymph nodes.

Chemokines have crucial roles in organ development and orchestration of leukocyte migration. The chemokine CCL22 is expressed constitutively at high levels in the lymph node, but the functional significance of this expression is so far unknown. Studying a newly established CCL22-deficient mouse, we demonstrate that CCL22 expression by dendritic cells (DCs) promotes the formation of cell-cell contacts and interaction with regulatory T cells (T reg) through their CCR4 receptor. Vaccination of CCL22-deficient mice led to excessive T cell responses that were also observed when wild-type mice were vaccinated using CCL22-deficient DCs. Tumor-bearing mice with CCL22 deficiency showed prolonged survival upon vaccination, and further, CCL22-deficient mice had increased susceptibility to inflammatory disease. In conclusion, we identify the CCL22-CCR4 axis as an immune checkpoint that is crucial for the control of T cell immunity.