Liling Wen

Increasing evidence has revealed a significant association between microorganisms and oral squamous cell carcinoma (OSCC). Porphyromonas gingivalis, the keystone pathogen in chronic periodontitis, is considered an important potential etiologic agent of OSCC, but the underlying immune mechanisms through which P. gingivalis mediates tumor progression of the oral cancer remain poorly understood. Our cohort study showed that the localization of P. gingivalis in tumor tissues was related to poor survival of patients with OSCC. Moreover, P. gingivalis infection increased oral lesion multiplicity and size and promoted tumor progression in a 4-nitroquinoline-1 oxide (4NQO)–induced carcinogenesis mouse model by invading the oral lesions. In addition, CD11b + myeloid cells and myeloid-derived suppressor cells (MDSCs) showed increased infiltration of oral lesions. Furthermore, in vitro observations showed that MDSCs accumulated when human-derived dysplastic oral keratinocytes (DOKs) were exposed to P. gingivalis, and CXCL2, CCL2, interleukin (IL)–6, and IL-8 may be potential candidate genes that facilitate the recruitment of MDSCs. Taken together, our findings suggest that P. gingivalis promotes tumor progression by generating a cancer-promoting microenvironment, indicating a close relationship among P. gingivalis, tumor progression of the oral cancer, and immune responses.

Immune alterations, such as neutrophil dysfunction, significantly affect the progression and outcome of periodontitis, a prevalent inflammatory disease. Despite this, the molecular mechanisms driving neutrophil dysregulation in periodontitis remain poorly understood. In this study, we demonstrate that CD300lf, a critical immune regulator, is markedly downregulated in neutrophils from a periodontitis mouse model and human patients. The loss of CD300lf accelerates neutrophil aging, as evidenced by increased reactive oxygen species production, the senescence-associated secretory phenotype with elevated IL-1β and S100A8/A9 levels, and heightened neutrophil extracellular trap formation. Mechanistically, CD300lf deficiency leads to MyD88 upregulation, indicating a shift toward a proinflammatory state. Inhibition of MyD88 effectively reduces periodontal inflammation in CD300lf-deficient mice. Furthermore, targeting CD300lf with its known ligand ceramide alleviates periodontitis and mitigates the aging phenotype of neutrophils. These findings underscore the critical role of the CD300lf/MyD88 axis in neutrophil homeostasis and suggest that modulation of CD300lf through ceramide presents a promising therapeutic strategy for periodontitis.

Despite achieving complete remission (CR) through surgery, chemoradiotherapy, targeted therapy, and other treatment modalities, breast cancer, particularly triple-negative breast cancer (TNBC) remains at a high risk of recurrence and metastasis. Enhancing anti-tumor immunity to eliminate residual tumor cells may reduce TNBC relapse. Our previous research indicated low-intensity pulsed ultrasound (LIPUS) can activate the anti‑tumor immunity. Here, we explore the potential of the suitable strategy with LIPUS, and the combination with an immune checkpoint inhibitor, anti-PD-1 antibody (αPD-1) to anti‑tumor immunity in TNBC. In the xenografted mouse model, different times (7, 14, 21, and 28d) and organs (spleen, bone marrow, spleen + bone marrow) of LIPUS were received to experimental groups. In 4T-1 low tumor burden model, after LIPUS irradiated different organs for 28d or combined with αPD-1, the tumor volume, lung metastasis, and survival time were observed. Flow cytometry, immunohistochemistry, immunofluorescence, multiplex immunofluorescence, and ELISA were performed to elucidate detailed impacts of LIPUS or combination treatment on anti‑tumor immunity. RNA-seq was used to preliminarily explore the biological mechanism of LIPUS. LIPUS inhibited the growth of 4T-1 xenografted, and the irradiation time was the main factor. In 4T-1 low tumor burden model, further studies had shown that LIPUS of spleen + bone marrow could best active anti‑tumor immunity primarily through CD8+ cytotoxic T lymphocytes (CD8+CTLs) and myeloid-derived suppressor cells (MDSCs), but not reduce the rate of tumor formation. LIPUS combined with αPD-1 not only reduce tumor formation rate but also further enhance anti‑tumor immunity mainly by means of CD8+CTLs, as well as led to significant changes in cytokines. The RNA-seq results also suggested the anti-tumor immune biological processes and signaling pathways were generated after LIPUS irradiating immune organs. Irradiating the spleen and bone marrow with LIPUS for 28 days may be an applicable treatment strategy, as it induces an increase in CD8+CTLs and a decrease in MDSCs, as well as an upregulation of mRNA levels in multiple immunomodulatory pathways. LIPUS combined with αPD-1 elicits a superior anti-tumor immune response and inhibits tumor formation in a 4T-1 low tumor burden model. This study provides a novel approach for treating TNBC after achieving CR by combining LIPUS with αPD-1.