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Simple Summary: Multiple myeloma (MM) is a plasma cell malignancy that develops in the bone marrow (BM) and the second-most-common blood cancer. Group 2 innate lymphoid cells (ILC2s) are emerging cytolytic immune effectors showing potent antitumor activity. In MM patients, ILC2s from peripheral blood possessed a cytotoxic arsenal, enabling them to kill MM cells via DNAM-1. In contrast, ILC2 resident in BM did not exert anti-myeloma activity, and instead became more susceptible to apoptosis. Specifically, MM cells led to ILC2 cell death by inducing and engaging the inhibitory receptor TIGIT. Collectively, ILC2s from MM patients displayed an imbalance in the DNAM-1/TIGIT axis, resulting in the conversion from a cytolytic to an exhausted profile. These findings support the employment of anti-TIGIT mAb to restore the survival and antitumor effects of ILC2s in MM. Background: Growing evidence attests to the multifaceted roles of group 2 innate lymphoid cells (ILC2s) in cancer immunity. They exhibit either pro- or anticancer activity depending on tumor type but their function in Multiple Myeloma (MM) is still not elucidated. Methods: The bone marrow (BM) and peripheral blood (PB) of patients (pts) with MM or precancerous conditions were collected, and specific properties of ILC2 subsets were assessed by flow cytometry. Results: By dissecting ILC2s according to c-Kit marker, we observed that NKp30 and NKG2D were mainly confined to c-Kithi ILC2s, while levels of DNAM-1 was significantly higher in fully mature c-Kitlo cells. Among the total MM-associated ILC2s (MM-ILC2s), we observed a significant increase in c-the Kitlo subset, but the expression of DNAM-1 in these cells was significantly reduced, especially in BM. Interestingly, MM-ILC2s from PB expressed granzyme B (GZMB), but its expression was impaired in BM-ILC2s. Accordingly, MM cells were susceptible to killing by MM-ILC2s derived from PB while eluding ILC2 surveillance in BM. Indeed, in MM-ILC2s derived from BM, the downregulation of DNAM-1 is accompanied by the upregulation of TIGIT, which mediate cell death in ILC2s upon recognition of the cognate ligands expressed by MM cells. These ILC2 changes appeared in clinical precursor conditions and eventually accumulated with disease progression. Conclusions: MM-ILC2s can act as cytolytic immune effectors that are fully competent in PB. However, MM cells shift ILC2 fate towards cell death in BM via the upregulation of TIGIT, thereby representing a potential therapeutic target to restore ILC2 antitumor activity. [ABSTRACT FROM AUTHOR]

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous family of immune cells including granulocytic (CD14neg/CD15+/HLA-DRneg) and monocytic subtypes (CD14+/CD15neg/HLA-DRneg). In the present study, we found a population of monocytes expressing the granulocyte marker CD15 that significantly increased in both peripheral blood (PB) and tumoral tissues of patients with colorectal cancer (CRC). Further phenotypical analysis confirmed the granulocytic-like features of this monocyte subpopulation that is associated with an increase in granulocyte–monocyte precursors (GMPs) in the PB of these patients (pts). Mechanistically, this granulocyte-like monocyte population suppressed NK cell activity by inducing TIGIT and engaging NKp30. Accordingly, an increased frequency of TIGIT+ NK cells with impaired functions was found in both the PB and tumoral tissue of CRC pts. Collectively, we provided new mechanistic explanations for tumor immune escape occurring in CRC by showing the increase in this new kind of MDSC, in both PB and CRC tissue, which is able to significantly impair the effector functions of NK cells, thereby representing a potential therapeutic target for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Polyvalent mechanical bacterial lysate is effective in the prevention of respiratory tract infections, although its mechanism of action is not entirely elucidated. Because epithelial cells constitute the frontline defense against infections, we investigated the molecular mechanisms of innate response exerted by bronchial epithelial cells in the presence of polyvalent mechanical bacterial lysate. By using primary human bronchial epithelial cells, we observed that polyvalent mechanical bacterial lysate was able to increase the expression of cellular adhesion molecules such as ICAM-1 and E-cadherin, as well as the expression of amphiregulin, a growth factor able to support human bronchial epithelial cell proliferation. Remarkably, polyvalent mechanical bacterial lysate promoted in human bronchial epithelial cells the de novo expression of human β-defensin-2, a major antimicrobial peptide, conferring them a direct antimicrobial activity. Moreover, polyvalent mechanical bacterial lysate–stimulated human bronchial epithelial cells provided signals for increased IL-22 production by innate lymphoid cells via IL-23, which could further contribute to the release of antimicrobial peptides by epithelial cells. In agreement with these in vitro data, the concentration of both IL-23 and antimicrobial peptides (human β-defensin-2 and LL-37) increased in the saliva of healthy volunteers after sublingual administration of polyvalent mechanical bacterial lysate. Altogether, these results indicate that polyvalent mechanical bacterial lysate administration might support mucosal barrier integrity and promote mechanisms of antimicrobial activity in airway epithelial cells. [ABSTRACT FROM AUTHOR]

Background: The Pfizer/BioNtech vaccine, also known as BNT162b2, was developed using a novel technology based on mRNA and protects against COVID-19 via induction of specific antibody and T-cell responses. Much less is known about the broader effects of this new class of vaccines on unconventional cellular components of the immune system., Objective: We aimed to characterize a subset of unconventional T cells emerging upon BNT162b2 mRNA vaccination., Methods: Peripheral blood from a total of 30 human healthy individuals who received two doses of the BNT162b2 mRNA vaccine was collected for the analysis of T cell compartment by using multiparametric flow cytometry and single-cell transcriptome analyses., Results: In the peripheral blood of individuals undergoing BNT162b2 vaccination, we observed a sizable fraction of CD8+ T cells expressing CD16, a low-affinity FcR for IgG. These cells were SARS-CoV-2 specific, characterized by interferon gamma (IFN-γ) response gene transcripts and stimulation through CD16 and other NK cell innate receptors elicited a functional response. Both CD16 and NKp30 could be induced on NKp80+ CD8+ T cells and the engagement of NKp80 in combination with CD16 resulted in synergic effects. CD16+ CD8+ T cells also showed a high expression of the inhibitory receptor GPR56, capable of limiting their activation via CD16., Conclusion: These data indicate that BNT162b2 COVID-19 vaccination provides an additional large fraction of antibody-dependent cellular cytotoxicity (ADCC)-capable effector cells, endowed with innate functions and therefore able to potentially counteract a much wider array of diseases, including cancer., (Copyright © 2025. Published by Elsevier Inc.)

Background: Respiratory viral infections are a leading cause of severe diseases and mortality; therefore, novel treatments effective for their prevention are highly requested. Here, we identified a broad-spectrum antiviral activity of a natural exopolysaccharide, EPS T14, purified from a marine thermotolerant strain of Bacillus licheniformis strain T14., Methods: The effects on human normal nasal epithelial cells (HNEpCs) following treatment with EPS T14 was evaluated at different time points and with increasing concentration of compound. To assess the antiviral properties, viability of HNEpCs treated with EPS T14 was analysed following infection with different respiratory viruses., Results: Neither toxicity nor pro-inflammatory properties were observed in vitro on HNEpCs treated with EPS T14 up to high concentrations, thus ensuring its safety. Cell culture-based assays revealed that treatment of HNEpCs with EPS T14 (used at 400ug/mL) results in efficient prevention of cell infection by different respiratory viruses through physically hindering the entry of the viruses via cell surface receptors. Interestingly, in addition to this prophylactic antiviral activity, EPS T14 also shows a long-lasting efficacy by inhibiting viral spread in the cell culture. Finally, combination of EPS T14 with a hypertonic saline solution shows a synergistic antiviral activity., Conclusion: EPS T14 can exert both prophylactic and therapeutic antiviral activity by blocking viral attachment to cellular receptors and could therefore represent a promising antiviral agent for preventing infections by different respiratory viruses., Competing Interests: The authors report no conflicts of interest in this work., (© 2024 Pezzino et al.)