Comprehensive Review: Unveiling the Pro-Oncogenic Roles of IL-1ß and PD-1/PD-L1 in NSCLC Development and Targeting Their Pathways for Clinical Management

Abstract

In the past decade, targeted therapies for solid tumors, including non-small cell lung cancer (NSCLC), have advanced significantly, offering tailored treatment options for patients. However, individuals without targetable mutations pose a clinical challenge, as they may not respond to standard treatments like immune-checkpoint inhibitors (ICIs) and novel targeted therapies. While the mechanism of action of ICIs seems promising, the lack of a robust response limits their widespread use. Although the expression levels of programmed death ligand 1 (PD-L1) on tumor cells are used to predict ICI response, identifying new biomarkers, particularly those associated with the tumor microenvironment (TME), is crucial to address this unmet need. Recently, inflammatory cytokines such as interleukin-1 beta (IL-1β) have emerged as a key area of focus and hold significant potential implications for future clinical practice. Combinatorial approaches of IL-1β inhibitors and ICIs may provide a potential therapeutic modality for NSCLC patients without targetable mutations. Recent advancements in our understanding of the intricate relationship between inflammation and oncogenesis, particularly involving the IL-1β/PD-1/PD-L1 pathway, have shed light on their application in lung cancer development and clinical outcomes of patients. Targeting these pathways in cancers like NSCLC holds immense potential to revolutionize cancer treatment, particularly for patients lacking targetable genetic mutations. However, despite these promising prospects, there remain certain aspects of this pathway that require further investigation, particularly regarding treatment resistance. Therefore, the objective of this review is to delve into the role of IL-1β in NSCLC, its participation in inflammatory pathways, and its intricate crosstalk with the PD-1/PD-L1 pathway. Additionally, we aim to explore the potential of IL-1β as a therapeutic target for NSCLC treatment.

Keywords: immune-checkpoint inhibitors (ICIs); interleukin-1 beta (IL-1β); non-small cell lung cancer (NSCLC); programmed death ligand 1 (PD-L1); therapeutic resistance.

Figure 1

Mechanism of the IL-1β pathway and its downstream effects. Legend: GSDMD—gasdermin D; IRAK—IL-1 receptor-associated kinase; MYD88—myeloid differentiation primary response 88; TRAF6—tumor necrosis factor receptor associated factor 6; MAPK—mitogen-activated protein kinase; IkB—inhibitor of nuclear factor kappa B; NF-kB (nuclear factor kappa B); AP-1—activator protein 1.

Figure 2

The effects of IL-1β on the tumor microenvironment. The figure depicts immunoregulatory cells altering the TME via secretion of IL-1β, which promote protumor changes including angiogenesis, immune suppression, and metastasis. Legend. TME—tumor microenvironment; APC—antigen-presenting cell; IL-1β—interferon 1-beta.

Figure 3

The proposed synergistic effect of co-inhibition of the IL-1β and PD-L1/PD-1 pathways. (1) Inhibition of IL-1β and PD-L1/PD-1 via monoclonal antibodies (inhibitors); (2) activation of cytotoxic T cells because of inhibition of IL-1β and PD-L1/PD-1 pathways; (3) anti-tumor immune response leading to decreased tumor metastasis and growth. Legend. TME—tumor microenvironment; PD-1—programmed cell death 1; PD-L1—programmed cell death ligand 1.