IL-1 Family Members in Bone Sarcomas

Abstract

IL-1 family members have multiple pleiotropic functions affecting various tissues and cells, including the regulation of the immune response, hematopoietic homeostasis, bone remodeling, neuronal physiology, and synaptic plasticity. Many of these activities are involved in various pathological processes and immunological disorders, including tumor initiation and progression. Indeed, IL-1 family members have been described to contribute to shaping the tumor microenvironment (TME), determining immune evasion and drug resistance, and to sustain tumor aggressiveness and metastasis. This review addresses the role of IL-1 family members in bone sarcomas, particularly the highly metastatic osteosarcoma (OS) and Ewing sarcoma (EWS), and discusses the IL-1-family-related mechanisms that play a role in bone metastasis development. We also consider the therapeutic implications of targeting IL-1 family members, which have been proposed as (i) relevant targets for anti-tumor and anti-metastatic drugs; (ii) immune checkpoints for immune suppression; and (iii) potential antigens for immunotherapy.

Keywords: Ewing sarcoma; IL-1 family; IL-1RAP; bone metastasis; chimeric-antigen-receptor-modified effectors; cytokines; immune escape; macrophages; osteosarcoma; tumor microenvironment.

Figure 1

Cell-intrinsic functions of IL-1RAP in EWS cells. (A) IL-1RAP interacts with the xCT/CD98 transporter system on the cell membrane to enhance exogenous cysteine uptake and maintain cysteine and glutathione pools. By preventing the generation of reactive oxygen species (ROS), they confer resistance to anoikis and protection against ferroptosis. (B) IL-1RAP can potentially enhance oncogenic signaling pathways by interacting with RTK that are highly expressed in EWS cells, such as FLT3 and c-Kit (created with Biorender.com).

Figure 2

Potential IL-1-family-related immune checkpoints and targets for CAR T/NK cell development. (A) Upon IL-1R or TLR engagement, the IRAK3 pseudokinase restrains myddosome and IRAK1 activation and blunts inflammation. IRAK3 can be removed using PROTAC degraders. (B) IL-1R8 behaves as a negative regulator of IL-1R and as a co-receptor for the anti-inflammatory cytokine IL-37, acting as a major checkpoint for NK function. The targeting of IL-1R8 could increase NK activity. (C) IL18BP is a decoy receptor for IL-18 and can be bypassed by a decoy-resistant IL-18 (DR-18), which is able to avoid IL18BP and bind the proper activating receptor, increasing type 1 immune responses. (D) Overexpression of IL-1RAP on CML/AML or EWS cells can be exploited for immunotherapy using anti-IL-1RAP antibodies or engineered IL-1RAP CAR T/NK cells (created with Biorender.com).