This is the first retrospective study involving analyses of baseline and on-treatment cytokine concentrations during ICI therapy. We found that pretreatment levels of IL-2, IL-17, and TNF-α as well as on-treatment levels of IL-2, IL-17, IFN-α, IFN-γ, and TNF-α were associated with immune-related adverse events. At the same time, on-treatment levels of IL-17 were related to the clinical response.
Growing evidence indicates that immunotoxicity profiles can be tied to specific cytokines that can amplify both pro- and anti-inflammatory immunity.10 Among Th2 cytokines, IL-2 is a key cytokine involved in promoting the proliferation of natural killer (NK) cells and T lymphocytes.11 Constantini et al.12 showed that a low serum IL-2 concentration measured at nivolumab initiation was associated with grade 3–4 toxicities in patients with advanced NSCLC; however, no association with progression-free survival (PFS) or overall survival (OS) was observed.
IL-5 is mainly produced by T helper-2 (Th2) lymphocytes and Group 2 innate lymphoid cells (ILC2s). It can increase antibody secretion by promoting the differentiation and growth of B cells and enhance the humoral immune response mediated by Th2 cells. Immunity to tumors is mainly governed by Th1-mediated cellular immunity. A Th1-Th2 drift will lead to immunosuppression and cancer development. 13
High concentrations of baseline serum IL-17 were identified in ipilimumab (anti-CTLA-4 Ab)-treated metastatic melanoma patients developing severe grade 3 gastrointestinal irAEs and may thus serve as a putative biomarker for defining both at-risk patients and the severity of ipilimumab-induced colitis.14
With close collaborations between academia and industry, recombinant IFNα2 became the first human immunotherapeutic approved by the US Food and Drug Administration (FDA) for cancer and, other than insulin, the first FDA-approved pharmaceutical product produced by recombinant DNA technology.15 IFNα has multiple antitumor properties, including direct tumor cell killing and stimulation of host immune cells, including dendritic cells and CD8+ T cells.16–18 However, no association has been found between the level of IFN-α and immune-related adverse events. According to our results, we can explain why overactivated immune cells can also damage other normal cells, which may lead to immune-related adverse events.
IFN-γ has various roles in immune reactions against tumors, including stimulation of tumor-infiltrating lymphocyte (TIL) proliferation and differentiation and secretion of IFN-γ following activation of T lymphocytes by tumor antigens.19 In contrast, IFN-γ may also promote the production of immunosuppressive molecules, which can have direct negative feedback on effector T cell function.20 During the elimination phase of the immune response against tumor cells, recruited tumor-infiltrating macrophages and NK cells produce various cytokines, including IFN-γ, to kill tumor cells.21 Therefore, an elevated level of IFN-γ may suggest increased cytotoxic activity against lung cancer tumor cells. However, this mechanism of action can also give rise to autoimmune-like side effects known as irAEs. In a study by Constantini et al. 12 IFN-γ levels at nivolumab initiation and two months later did not show correlations with the objective response rate, clinical benefit, or survival, which is consistent with our study.
In the tumor microenvironment, TNF-α acts as an inflammatory mediator involved in tumorigenesis.22,23 Soluble TNF-α is also involved in the activation of neutrophils, macrophages, and lymphocytes at damaged and infected sites24. In rheumatoid arthritis, the inflammatory response is associated with increased secretion of tumor necrosis factor (TNF)-α and interleukin (IL)-6, whereas psoriasis involves the production of TNF-α, IL-17, and IL-23, in affected tissues.25
Perez-Ruiz et al. 26found that enriched TNF gene expression was enriched in colonic mucosal tissue biopsies from CPI-treated cancer patients who developed colonic irAEs compared to healthy controls, which was further confirmed in another study by single-cell RNA sequencing, where melanoma patients who developed CPI-induced colitis displayed an increased abundance of myeloid cells in the colon with an enriched TNF-α gene signature compared to CPI-treated melanoma patients without colitis and to healthy controls.27