Critical Reviews in Immunology最新文献

Anorectal mucosal melanoma (AMM) poses a significant challenge as a rare and aggressive cancer with limited treatment options. The current standard treatments for AMM have notable drawbacks, often leading to disease recurrence and progression, ultimately resulting in a poor prognosis for patients with advanced AMM. The critical necessity for innovative therapeutic strategies to enhance outcomes in AMM cases is evident. In this report, a groundbreaking personalized (n) of one approach was detailed for the treatment of advanced mucosal melanoma. This pioneering method involves utilizing low-dose immunotherapy as an immune regenerative medicine (IRM) regimen. The treatment plan is tailored based on liquid biopsy analysis of plasma-derived cell-free circulating tumor DNA (ctDNA) with mutational profiling. This approach aims to enhance the patient's immune response to the disease, reduce tumor burden, and minimize adverse effects. This compelling case study showcased a 66-year-old male with recurrent stage III AMM. Despite undergoing standard therapies with multiple surgeries, radiation therapy, and immune checkpoint inhibitor (ICI) treatment, disease progression persisted. However, post low-dose interleukin-2 (IL-2) immunotherapy, notable improvements were observed in the patient's immune function, particularly in natural killer (NK) cell number and activity. Additionally, the cancer exhibited regression, highlighted by a significant decrease in NRAS Q61R driver mutations and the absence of the BRCA2 A3012P mutation. These encouraging results suggest that personalized precision immunotherapy focusing on NK cells could potentially revolutionize the treatment landscape for AMM patients who have exhausted conventional therapies. Notably, the patient experienced minimal side effects and avoided toxicity-related complications. While further research is essential to validate these findings, the prospect of this approach as a viable management strategy for this aggressive cancer type is promising.

IL-2 agonists significantly modulate T cell regulation, impacting activation, proliferation, differentiation, and immune homeostasis. Interleukin-2 (IL-2) is crucial for T cell growth and function, binding to the IL-2 receptor to trigger signaling pathways that balance immune responses. IL-2 promotes the expansion of effector T cells and enhances regulatory T cells (Tregs), preventing autoimmune responses. This review examines the mechanisms of IL-2 agonists on T cell regulation, including their roles in cytotoxic T cells and Tregs proliferation, and immune homeostasis. Clinically, IL-2 agonists show promise in treating autoimmune diseases by boosting Treg function and in cancer immunotherapy by enhancing cytotoxic T cell activity. Optimizing IL-2 therapies to balance these effects is ongoing. IL-2 agonists are pivotal in modulating T cell responses with significant therapeutic potential for autoimmunity and cancer. Understanding IL-2 signaling is crucial for developing targeted treatments leveraging this cytokine's benefits.

In this paper, we compared the ability to expand/supercharge NK cells (sNK) by either processed osteoclasts (pOCs) or live osteoclasts (OCs). pOCs induced similar levels of cell expansion in NK cells compared to live OCs. pOC-generated sNK cells exhibited lower lysis of oral squamous carcinoma stem-like cells (OSCSCs) tumors in comparison to live OC-generated sNK cells. Slightly lower levels of IFN-γ secretion were also observed in pOC-generated sNK cells when compared to live OC-generated sNK cells. Cytotoxic function and secretion levels of IFN-γ remained low in pOC-sNK cultures compared to OC-sNK cultures even after adding the supernatants harvested from live OCs to pOC-sNK cultures. pOCs were equally capable of selecting CD8+ T cells in sNK cell cultures when compared to live OCs. Overall, even though live OCs are capable of activating slightly better than the processed osteoclasts, the use of pOCs is preferable for the expansion of sNK cells due to shorter NK expansion period, higher cost-effectiveness, and faster availability for patient infusion.

Diffuse intrinsic pontine glioma (DIPG) is the common cause of death in pediatric patients. In this report, we discussed the role of supercharged NK (sNK) cells alone or in combination with other therapies to target such aggressive pediatric brain tumors, suggesting the potential use of sNK cells alone as a therapeutic strategy in treating and preventing the recurrence of aggressive pediatric brain tumors.

Immunotherapy has shown significant promise in the clinical management of prostate cancer (PCa), and prostaglandin E receptor 4 (EP4) is a key governing factor in PCa progression. However, the molecular mechanisms by which EP4 influences immunotherapy in PCa have yet to be elucidated. This investigation was designed to unravel the specific mechanisms through which EP4 affects the killing ability of CD8+ T cells against PCa cells. Immunohistochemistry was utilized to assay the expression of EP4, programmed death ligand 1 (PD-L1), and CD8+ T cell infiltration in tissue samples, and quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot (WB) were used to evaluate EP4 expression in cells. PCa cell lines with either EP4 knockdown or overexpression were co-cultured with CD8+ T cells. Lactase dehydrogenase toxicity assays were employed to measure CD8+T cell killing ability, and ELISA was employed to measure interferon-gamma (IFN-γ), tumor necrosis factor-alpha (TNF-α), and interleukin-2 (IL-2) levels. Expression of T cell exhaustion markers was detected by flow cytometry. Rescue experiments were conducted utilizing 3-methyladenine [a phosphoinositide 3-kinase (PI3K) inhibitor] and PD-L1 knockdown. The impact of EP4 overexpression on the PI3K/AKT signaling pathway-mediated PD-L1 expression and its subsequent modulation of CD8+ T cell killing ability against PCa cells was assessed through qRT-PCR, WB, flow cytometry, and immunofluorescence. EP4 exhibited a substantial upregulation in both PCa tissues and cells, displaying a positive correlation with PD-L1 expression and a converse negative correlation with the infiltration of CD8+ T cells. Knockdown of EP4 expression inhibited CD8+ T cell exhaustion, enhanced CD8+ T cell killing ability against PCa cells, increased the levels of IFN-γ, IL-2, and TNF-α, and decreased PD-L1 expression. Conversely, EP4 overexpression resulted in opposite effects, but treatment with 3-methyladenine mitigated EP4-induced promotion of PD-L1, p-AKT, and t-AKT expression. Furthermore, the knockdown of PD-L1 mitigated the inhibitory impact of EP4 overexpression on the killing ability of CD8+ T cell and the levels of IFN-γ, IL-2, and TNF-α, all while leaving the expression of p-AKT and t-AKT unaffected. EP4 was significantly overexpressed in PCa and activated PD-L1 expression via the PI3K/AKT signaling pathway, thereby suppressing the activity of CD8+ T cells.

This study aims to explore the relationship between tumor size, lymph node status, and ER/PR/HER2 expression in breast cancer patients. A total of 117 breast cancer patients who underwent surgery at our hospital were selected as the research objects. All patients underwent ipsilateral axillary lymph node dissection or sentinel lymph node biopsy during surgery. Pathological data and ultrasound features of primary lesions were collected. Univariate and multivariate logistic regression analyses were performed to evaluate the relationship between tumor size, lymph node status, and ER/PR/HER2 expression, as well as to identify the risk factors for lymph node metastasis in breast cancer patients. Among the 117 patients, 48 were positive for ipsilateral axillary lymph node metastasis and 69 were negative. Univariate analysis showed no significant correlation between age, PR status, molecular subtype, and lymph node metastasis (P > 0.05). Univariate analysis showed that tumor size, pathological type, menopausal status, Ki67 expression, HER2 status, and ER status were significantly associated with lymph node metastasis (P < 0.05). Logistic regression further identified tumor size [odds ratio (OR) = 1.809, 95% confidence interval (CI): 1.075-3.428, P = 0.018), pathological type (OR = 2.947, 95% CI: 1.241-7.536, P = 0.012), Ki67 expression (OR = 15.923, 95% CI: 3.219-74.512, P = 0.001), HER2 status (OR = 2.509, 95% CI: 1.586-5.769, P = 0.015), and ER status (OR = 3.226, 95% CI: 1.408-8.277, P = 0.007) as independent risk factors for lymph node metastasis. This study reveals that lymph node metastasis in breast cancer patients is significantly associated with larger tumor size (> 20 mm), invasive tumor type, higher Ki67 expression, HER2 positivity, and ER negativity. These findings emphasize the importance of incorporating these risk factors into clinical assessments to guide individualized treatment planning. By identifying patients with elevated lymph node metastasis risk, clinicians can better tailor treatment strategies to improve patient outcomes and optimize therapeutic interventions.

Objective: This study aimed to probe the role of Shenling Baizhu powder (SLBZP) in inhibiting breast cancer (BC) lung metastasis, focusing on epithelial-to-mesenchymal transition (EMT) and ferroptosis.

Methods: BC 4T1 cells were treated with low (3.13 µg/mL) and high (12.5 µg/mL) doses of SLBZP. Cell proliferation, migration, and invasion were assessed via CCK-8 and transwell assays. Intracellular reactive oxygen species (ROS), malondialdehyde (MDA), and Fe2+ levels were measured using commercial kits. Western blot was used to detect EMT markers (E-cadherin, N-cadherin, Vimentin). In vivo, Balb/c mice injected with 4T1 cells received SLBZP or cyclophosphamide (CTX). Tumor volume, mass, and lung metastases were recorded. MDA, Fe2+, EMT markers, and ferroptosis-related GPX4 were evaluated in tumor tissues.

Results: SLBZP dose-dependently suppressed 4T1 cell proliferation, migration, invasion, and EMT, as indicated by upregulated E-cadherin and downregulated N-cadherin and Vimentin. SLBZP increased cellular ROS, MDA, and Fe2+ levels (P < 0.05). In vivo, SLBZP and CTX significantly reduced tumor burden and lung metastases, elevated MDA, Fe2+, and E-cadherin, and decreased N-cadherin, Vimentin, and GPX4 in tumor tissues (P < 0.05).

Conclusion: SLBZP inhibits BC lung metastasis by modulating EMT and ferroptosis, highlighting its therapeutic potential.

Stemming from human immune organs, tonsil-derived mesenchymal stem cells (TMSCs) hold unique strengths in differentiation potential and immune regulatory functions. These characteristics make them valuable for therapeutic applications, particularly in regenerative medicine and autoimmune disease treatment, as they can modulate immune responses and promote tissue repair. Their ability to interact with various cell types and secrete a range of bioactive molecules further enhances their role in orchestrating healing processes, making them a promising avenue for innovative therapies aimed at restoring balance in the immune system and facilitating recovery from injury or disease. TMSCs are crucial elements of the tonsillar microenvironment, playing a key role in preserving the balance of the immune system. They regulate immune responses by producing cytokines and growth factors, influencing neighboring immune cells, and facilitating communication within tonsillar tissue to maintain a controlled response to pathogens and prevent excessive inflammation. As understanding of TMSCs continues to evolve, their integration into clinical practices could revolutionize approaches to treating a wide array of conditions, highlighting the importance of continued investigation in this promising field.

Background: Sarcoidosis is a complex inflammatory disease of unknown etiology affecting mostly the lungs and poses a significant diagnostic challenge, particularly in regions where tuberculosis (TB) is endemic. The diagnostic complexity intensifies due to shared clinical and radiological features between sarcoidosis and TB, as well as similarities with idiopathic pulmonary fibrosis (IPF) in cases that progress to pulmonary fibrosis. Accurately distinguishing between these diseases is critical for timely and effective patient management.

Objective: This study breaks new ground by evaluating the diagnostic power of the bronchoalveolar lavage (BAL) CD4/ CD8 ratio, along with key activation and memory markers to differentiate sarcoidosis from TB, IPF, and other-interstitial lung diseases (ILDs).

Methods: A cohort of 68 patients with ILDs, including sarcoidosis (n = 37), TB (n = 19), IPF (n = 6), and Other-ILDs (n = 6) were assessed. The CD4/CD8 ratio and a panel of activation and memory markers were analyzed through flow cytometry.

Results: Sarcoidosis exhibited a significantly higher CD4/CD8 ratio compared to those with TB, IPF, and Other-ILDs. An optimal cutoff value of 3.7 for the CD4/CD8 ratio in sarcoidosis with an area under the ROC curve (AUC) of 0.7%, had a specificity of 96.8%, and a sensitivity of 43.2%. In addition, a significant difference was detected in CD38, CD45RA, CD45RO, and CD62L expression.

Conclusion: Combining the CD4/CD8 ratio (> 3.7) with the expression of CD38, CD62L, and memory markers is a promising new tool for the differential diagnosis of sarcoidosis.