The anti-tumoral effect of neutrophils on adaptive immune responses in tumor-draining lymph nodes in head and neck cancer
Neutrophils play significant, yet versatile, roles in head and neck squamous cell carcinoma (HNC), influencing patient prognosis in various ways, particularly through their interactions with adaptive immune cells in tumor-draining lymph nodes (TDLNs).
Here, with combined three published studies, we shed a light on the crucial and multifaceted roles of neutrophils in HNC progression and patient prognosis, emphasizing the importance of their interactions with B and T cells in tumor-draining lymph nodes, and the influence of type I IFN signaling on their anti-tumor functions. First, we demonstrated the presence of B-helper neutrophils (NBH) in the TDLNs of HNC patients and their impact on B cell activity. Using flow cytometry, quantitative polymerase chain reaction (qPCR), and immunohistochemistry, we found that NBH presence correlates with increased B cell proliferation and elevated expression of activation-induced cytidine deaminase (AID). Importantly, we showed that patients with higher frequencies of NBH in B cell follicles of TDLNs exhibit significantly better outcome. These findings underscore the role of neutrophils in T cell-independent activation of the adaptive immune system through B cell stimulation, highlighting their positive impact on patient prognosis. Next, by comparing the neutrophils in TDLNs according to the stages of metastasis, we identified the stage-dependent functions of neutrophils during HNC progression. In metastasis-free stages (N0), neutrophils acquire an antigen-presenting phenotype and stimulate T cells, thus contributing positively to 5-year survival predictions. Conversely, in metastatic stages (N1-N3), we showed that neutrophils suppress T cell responses, leading to poor prognosis. With further analyses, we discovered that LN metastases release granulocyte-macrophage colony-stimulating factor (GM-CSF), which activates signal transducer and activator of transcription 3 (STAT3) to induce programmed death-ligand 1 (PD-L1) expression on immunosuppressive neutrophils. This dual role of neutrophils as both positive and negative regulators of anti-cancer immunity suggests that enhancing their immunostimulatory functions could be beneficial in cancer therapy. Lastly, we observed that type I interferon (IFN) signaling is essential for the anti-tumor activity of neutrophils in TDLNs. In mice deficient in type I IFNs (Ifnar1-/-), increased tumor growth and metastatic spread are observed due to a pro-tumoral neutrophil bias. Live imaging and functional analyses revealed that impaired IFNAR1 signaling diminishes neutrophil-T cell interactions, thus inhibiting T-cell proliferation and activation, and promoting tumor growth. Conversely, activating IFN signaling independently of missing IFNAR using IFN-λ enhances neutrophil immunostimulatory capacity and suppresses tumor growth. These findings highlight the critical role of functional type I IFN signaling in neutrophil-mediated anti-tumor immunity in TDLNs and suggest potential therapeutic opportunities in HNC.
In summary, these observations prove the importance of anti-tumoral neutrophil activity in TDLNs for a comprehensive treatment of HNC by highlighting the complex and dynamic roles of neutrophils in cancer progression particularly focusing on their interactions with lymphocytes.
Here, with combined three published studies, we shed a light on the crucial and multifaceted roles of neutrophils in HNC progression and patient prognosis, emphasizing the importance of their interactions with B and T cells in tumor-draining lymph nodes, and the influence of type I IFN signaling on their anti-tumor functions. First, we demonstrated the presence of B-helper neutrophils (NBH) in the TDLNs of HNC patients and their impact on B cell activity. Using flow cytometry, quantitative polymerase chain reaction (qPCR), and immunohistochemistry, we found that NBH presence correlates with increased B cell proliferation and elevated expression of activation-induced cytidine deaminase (AID). Importantly, we showed that patients with higher frequencies of NBH in B cell follicles of TDLNs exhibit significantly better outcome. These findings underscore the role of neutrophils in T cell-independent activation of the adaptive immune system through B cell stimulation, highlighting their positive impact on patient prognosis. Next, by comparing the neutrophils in TDLNs according to the stages of metastasis, we identified the stage-dependent functions of neutrophils during HNC progression. In metastasis-free stages (N0), neutrophils acquire an antigen-presenting phenotype and stimulate T cells, thus contributing positively to 5-year survival predictions. Conversely, in metastatic stages (N1-N3), we showed that neutrophils suppress T cell responses, leading to poor prognosis. With further analyses, we discovered that LN metastases release granulocyte-macrophage colony-stimulating factor (GM-CSF), which activates signal transducer and activator of transcription 3 (STAT3) to induce programmed death-ligand 1 (PD-L1) expression on immunosuppressive neutrophils. This dual role of neutrophils as both positive and negative regulators of anti-cancer immunity suggests that enhancing their immunostimulatory functions could be beneficial in cancer therapy. Lastly, we observed that type I interferon (IFN) signaling is essential for the anti-tumor activity of neutrophils in TDLNs. In mice deficient in type I IFNs (Ifnar1-/-), increased tumor growth and metastatic spread are observed due to a pro-tumoral neutrophil bias. Live imaging and functional analyses revealed that impaired IFNAR1 signaling diminishes neutrophil-T cell interactions, thus inhibiting T-cell proliferation and activation, and promoting tumor growth. Conversely, activating IFN signaling independently of missing IFNAR using IFN-λ enhances neutrophil immunostimulatory capacity and suppresses tumor growth. These findings highlight the critical role of functional type I IFN signaling in neutrophil-mediated anti-tumor immunity in TDLNs and suggest potential therapeutic opportunities in HNC.
In summary, these observations prove the importance of anti-tumoral neutrophil activity in TDLNs for a comprehensive treatment of HNC by highlighting the complex and dynamic roles of neutrophils in cancer progression particularly focusing on their interactions with lymphocytes.