Abstract
Simple SummaryHost immunity has established its role in deciding the course of cancer evolution. As cellular and molecular components in the tumor microenvironment peripherally appear to be at a constant interplay, favoring either tumor control or progression, it is vital to decrypt the immunity elements, which demonstrate the potential to be harnessed towards cancer elimination. Head and neck cancer has been characterized as densely immune infiltrated but at the same time a highly immunosuppressive malignancy due to a negative equilibrium between active and dysfunctional immune cell populations. B-cells constitute the cornerstone of humoral immunity; however, their role in cancer has been vastly overlooked in comparison to other immune subtypes and reports from multiple studies fail to show agreement on their prognostic impact. This review focuses on the role of B-cells on head and neck cancer with the aim to highlight their effect on anti-cancer immunity, as well as their possible impact on immunotherapy outcomes.Head and neck cancer comprises a heterogenous, highly immune infiltrated malignancy, defined by a predominantly immunosuppressive tumor microenvironment (TME). In recent years, PD-1/PD-L1 immune checkpoint inhibitors have become the standard of care treatment, either as monotherapy or in combination with chemotherapy agents, thus revolutionizing the therapeutic landscape of recurrent/metastatic disease. As a result, preclinical research is increasingly focusing on TME composition and pathophysiology, aiming to comprehensively characterize the specific elements and interactions affecting anti-tumor immunity, as well as to unveil novel predictive biomarkers of immunotherapy outcomes. While T lymphocytic populations have been vastly explored regarding their effect on cancer development, B-cells constitute a far less investigated, yet possibly equally important, aspect of cancer immunity. B-cell presence, either as single cells or as part of tertiary lymphoid structures within the TME, has been associated with several anti-tumor defense mechanisms, such as antigen presentation, antibody production and participation in antibody-dependent cellular cytotoxicity, and has demonstrated prognostic significance for multiple types of malignancies. However, immunoregulatory B-cell phenotypes have also been identified both peripherally and within malignant tissue, bearing inhibitory effects on numerous immune response processes. Consequently, B-cells and their subsets demonstrate the potential to become valuable cancer biomarkers and acquire a leading role in future therapeutic strategies.
Highlights
The constantly fluctuating interactions between host immunity and cancer cells have been well established as a key component of disease control or progression, as well as a field for the development of novel anti-cancer therapeutics
B-cells have been reported to account for one-fourth of all infiltrating cells in some malignancies [18], and most importantly, to exhibit surface expression of programmed cell death-1 (PD-1), PD-L1, CTLA-4 and B-7 molecules at various levels, suggesting that their activity could be modified by currently approved immunotherapy agents [19,20,21,22,23]
The analysis showed either a positive or neutral prognostic effect of tumor-infiltrating CD20+ B-cells (TIL-B) in ovarian, breast, gastric, hepatocellular, soft tissue sarcoma, esophageal and biliary tract cancer while in NSCLC, colorectal, melanoma pancreatic and Head and Neck Squamous Cell Carcinoma (HNSCC), evidence of TIL-B prognostic significance were contradicting [58]
Summary
The constantly fluctuating interactions between host immunity and cancer cells have been well established as a key component of disease control or progression, as well as a field for the development of novel anti-cancer therapeutics. The distinct anatomical location of HNSCC, favoring rich lymphatic vasculature development, and the hypoxic conditions identified within these tumors, in addition to their main risk factors, including HPV positivity, smoking and alcohol consumption, lead to the formation of an “immune inflamed” yet simultaneously immunosuppressive TME [29,30,31] In this setting, immune cell subtypes, among T-cells, tumor-associated macrophages and neutrophils, have been widely characterized for their immune-stimulatory (CD3+, CD8+, M1 macrophages, NK cells) or anti-inflammatory function (CD4+/Foxp3+ T cells, myeloid-derived suppressor cells, M2 macrophages, N2 neutrophils) with respective positive or negative effects on HNSCC outcomes [32,33,34], while B-cells have only recently attracted researchers’ interest with inconclusive results regarding their prognostic role, so far [35]. The above findings underscore the need to investigate TLS as potential predictive biomarkers of response to immunotherapy in other malignancies as well, including HNSCC
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