Exploring the frontiers: tumor immune microenvironment and immunotherapy in head and neck squamous cell carcinoma

Abstract

The global prevalence of head and neck malignancies positions them as the sixth most common form of cancer, with the head and neck squamous cell carcinoma (HNSCC) representing the predominant histological subtype. Despite advancements in multidisciplinary approaches and molecular targeted therapies, the therapeutic outcomes for HNSCC have only marginally improved, particularly in cases of recurrent or metastatic HNSCC (R/MHNSCC). This situation underscores the critical necessity for the development of innovative therapeutic strategies. Such strategies are essential not only to enhance the efficacy of HNSCC treatment but also to minimize the incidence of associated complications, thus improving overall patient prognosis. Cancer immunotherapy represents a cutting-edge cancer treatment that leverages the immune system for targeting and destroying cancer cells. It's applied to multiple cancers, including melanoma and lung cancer, offering precision, adaptability, and the potential for long-lasting remission through immune memory. It is observed that while HNSCC patients responsive to immunotherapy often experience prolonged therapeutic benefits, only a limited subset demonstrates such responsiveness. Additionally, significant clinical challenges remain, including the development of resistance to immunotherapy. The biological characteristics, dynamic inhibitory changes, and heterogeneity of the tumor microenvironment (TME) in HNSCC play critical roles in its pathogenesis, immune evasion, and therapeutic resistance. This review aims to elucidate the functions and mechanisms of anti-tumor immune cells and extracellular components within the HNSCC TME. It also introduces several immunosuppressive agents commonly utilized in HNSCC immunotherapy, examines factors influencing the effectiveness of these treatments, and provides a comprehensive summary of immunotherapeutic strategies relevant to HNSCC.

Keywords: Head and neck squamous cell carcinoma; Immunotherapy; Tumor microenvironment.

Fig. 1

The immune microenvironment of tumors primarily consists of various types of immune-related cells and their interactions. A. Common types of immune-related cells present in the tumor's immune microenvironment. B. The interactions among these cells constitute the anti-tumor immune activity in the immune microenvironment. CTL cytotoxic T lymphocyte, Th T helper cell, NK cells natural killer cells, MHC major histocompatibility complex, TCR T cell receptor, TNF tumor necrosis factor, IFN interferon, PFN perforin

Fig. 2

The interaction between PD-1 and PD-L1 leads to a suppression of T lymphocyte function. T cells engage in an interaction with antigen-presenting cells (APCs) through the binding of their surface T cell receptor (TCR) with major histocompatibility complex (MHC) molecules expressed on APCs. The binding of programmed cell death protein 1 (PD-1) with programmed death ligand 1 (PD-L1) leads to an inhibitory signaling pathway. This occurs through the interaction between the immunoreceptor tyrosine-based inhibitory motif (ITIM) of PD-1 and the SH2 domain-containing protein tyrosine phosphatase 2 (SHP-2), resulting in the attenuation of TCR signaling. The diagram also depicts the interaction between another immune checkpoint, cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), and the molecule B7-1. This interaction also transmits a negative regulatory signal, further modulating the activity of T cells

Fig. 3

TME encompasses various components, including stromal cells (cancer-associated fibroblasts, endothelial cells, and pericytes), extracellular matrix (ECM), immune cells, and inflammatory cells (T, B, and NK lymphocytes, DCs, macrophages, and myeloid-derived suppressor cells)

Fig. 4

MDSCs contribute multifaceted roles in tumor progression. MDSCs suppress T-cell responses via the release of inhibitory factors, such as arginase 1 (ARG1), inducible nitric oxide synthase (iNOS), and reactive oxygen species (ROS). They facilitate the induction of Tregs and remodel the TME through the secretion of molecules like interleukin-10 (IL-10), transforming growth factor-beta (TGF-β), and vascular endothelial growth factor (VEGF), thereby promoting angiogenesis and metastatic dissemination

Fig. 5

The cytokines produced within the TME can generate macrophages with distinct physiological characteristics. Cytokines such as IL-4 (interleukin 4), IL-13, and IL-10 can induce monocytes to differentiate into tumor-promoting (M2-type) macrophages, while IFN-γ (interferon γ) induces the formation of macrophages with anti-tumor properties (M1-type). M2-type macrophages release molecules such as IL-1β, IL-6, IL-8, VEGFs (vascular endothelial growth factors), and MMPs (matrix metalloproteinases), promoting Th2-type immune responses. On the other hand, M1-type macrophages produce TNF-α, IL-12, reactive nitrogen, and oxygen intermediates, stimulating Th1-type immune responses, and exerting inhibitory effects on tumor formation