draining-lymph-node-metastasis-model-for-assessing-dynamics-antigen

Draining Lymph Node Metastasis Model for Assessing the Dynamics of Antigen-Specific CD8<sup>+</sup> T Cells During Tumorigenesis

Tumor antigen-specific CD8+ T cells from draining lymph nodes gain an accumulating importance in mounting anti-tumor immune response during tumorigenesis. ...

Third Military Medical University

Refractory ischemic ulcers that occur in patients with diabetes present a major clinical challenge. Embryonic artery cluster of differentiation 133 cells (EACCs) may promote the healing of diabetic ulcers; however, the high glucose environment in the diabetic ulcers decreases the survival rate of transplanted EACCs and inhibit their biological function. Furthermore, microcirculation in diabetic ischemic ulcers is impaired, which inhibits the beneficial effect of EACCs. In the current study, the Sirt1 agonist SRT1720 was selected as a therapeutic drug and loaded into a dressing composed of PLGA, collagen and silk (PCSS) formed using electrospinning technology. EACCs were seeded onto the PCSS dressing and this was used to treat diabetic ulcers. The results indicated that SRT1720 promotes the proliferation of EACCs, enhances the secretion of vascular endothelial growth factor A, interluekin 8 and basic fibroblast growth factor, and inhibits the secretion of tumor necrosis factor α. Furthermore, SRT1720 promoted the paracrine function of EACCs and promoted the proliferation and migration of human umbilical vein endothelial cells. PCSS induced the steady release of SRT1720 over a 15-day period and PCSS seeded with EACCs (PCSS-EACCs) were transplanted into the diabetic ischemic ulcers of mice with diabetes. The results of these experiments indicated that angiogenesis and the healing of diabetic ischemic ulcers was significantly improved following the transplantation of PCSS-EACCs. Therefore, PCSS-EACCs may be a novel and effective treatment for diabetic ischemic ulcers.

A novel dressing seeded with embryonic artery CD133 cells and loaded with the Sirt1 agonist SRT1720 accelerates the healing of diabetic ischemic ulcers.

Letter to Editor: Association Between Postoperative Liver Dysfunction and Blood-Derived MicroRNA Signatures.

Pancreatic ductal adenocarcinoma (PDAC) is a malignant tumor with very poor prognosis. Therefore, it is important to fully understand the molecular mechanism underlying its occurrence and development. Pumilio RNA-binding family member 1 (PUM1) has been reported to function as an oncogene in ovarian cancer and nonsmall cell lung cancer. However, its role and mechanism in PDAC have not been fully illuminated. Here, we found that the PUM1 protein levels were higher in PDAC tissues than in adjacent tissues and that PUM1 levels were significantly associated with TNM stage and overall survival time, indicating a correlation between high PUM1 expression and poor prognosis in patients with PDAC. In vitro and in vivo assays showed that PUM1 knockdown inhibited cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), and promoted apoptosis in MIA PaCa-2 and PANC-1 cells. Through cDNA microarrays and ingenuity pathway analysis, we found that the activation of the eIF2 signaling pathway significantly correlated with PUM1 knockdown. These results were further confirmed by the increased levels of key components of the eIF2 signaling pathway, p-PERK, p-EIF2A, and ATF4 in PUM1 knockdown cells. We also found that PUM1 levels have a significant negative correlation with p-PERK levels in PDAC tissues and that PERK overexpression inhibited cell proliferation, migration, invasion, and EMT, and promoted apoptosis in vitro. Moreover, a PERK inhibitor alleviated the effects of PUM1 knockdown on cell proliferation, apoptosis, migration, invasion, and EMT. Taken together, our results revealed that PUM1 knockdown suppressed cell growth, invasion, and metastasis, and promoted apoptosis by activating the PERK/eIF2/ATF4 signaling pathway in PDAC cells. PUM1 could be a potential target to develop pharmaceuticals and novel therapeutic strategies for the treatment of PDAC.

PUM1 knockdown prevents tumor progression by activating the PERK/eIF2/ATF4 signaling pathway in pancreatic adenocarcinoma cells.

BACKGROUND Comorbidities are reportedly related to the survival of patients with non-small cell lung cancer (NSCLC). The purpose of this study was to explore the impact of comorbidity, assessed by the Charlson comorbidity index (CCI) and the simplified comorbidity scores (SCS) on clinical outcomes of patients with NSCLC treated with immune checkpoint inhibitors. MATERIAL AND METHODS Sixty-six patients with NSCLC who received programmed cell death protein 1 (PD1) inhibitors in our institution in the past 2 years were enrolled in this retrospective study. Data on comorbidity (CCI and SCS) and clinical outcomes, including progression-free survival (PFS), immunotherapy responses, and immunotherapy-related adverse events, were analyzed. RESULTS The disease control rate was obviously higher among patients in the CCI <1 group than the CCI ≥1 group (P<0.001), but were similar between the SCS <8 group and SCS ≥8 group (P=0.585). The median PFS in the CCI <1 group was 271.0 days (95% CI: 214.3-327.7 days) compared with 232.0 days (95% CI: 66.2-397.8 days) for the CCI ≥1 group (P=0.0084). However, the median PFS showed no difference between the groups with SCS <8 at 271.0 days (95% CI: 138.7-403.3 days) versus SCS ≥8 at 222.0 days (95% CI: 196.2-247.8 days), P=0.2106). The incidence of adverse events was similar among patients with high versus low comorbidity indexes (CCI: 35.8% versus 23.6%, P=0.286, respectively; and SCS: 28.0% versus 29.3%, respectively, P=0.912). CONCLUSIONS The comorbidity burden might be a predictor for survival in patients with NSCLC undergoing PD1 inhibitor immunotherapy.

Effect of Comorbidity on Outcomes of Patients with Advanced Non-Small Cell Lung Cancer Undergoing Anti-PD1 Immunotherapy.

Pancreatic cancer is one of the deadliest cancers in the world, and pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of all cases. Human positive coactivator 4 (PC4) is a transcriptional coactivator that has been associated with the development and progression of several tumors. However, no studies investigated the potential role of PC4 in PDAC.

Human Positive Coactivator 4 Affects the Progression and Prognosis of Pancreatic Ductal Adenocarcinoma via the mTOR/P70s6k Signaling Pathway.

Refractory ulcers are a major challenge in the treatment of a diabetic foot, because of the immunodeficient, ischemic and high-glucose microenvironment. Inflammatory memory peptides, which were extracted from the immune mediator absent in melanoma 2 (AIM2), could effectively improve the immunodeficient microenvironment and special angiogenic peptides could effectively promote angiogenesis. Moreover, the gut flora  () participates in diabetic metabolism and could decrease high-glucose levels. In this research, a polypeptide skeleton (PPS) was synthesized based on 3,4-dihydroxyphenylalanine (DOPA) and peptides, forming the hydrophilic and hydrophobic parts. Inflammatory memory peptides and angiogenic peptides were synthesized and conjugated with the PPS, which then formed an anisotropic hydrogel through the self-assembling of β-sheet peptides based on hydrophobicity and DOPA oxidation.  was seeded into the hydrogel and transported into diabetic ischemic ulcers through subcutaneous injection, and the healing of diabetic ischemic ulcers was promoted. The inflammatory memory peptides were released based on the  enzyme response, and they firstly improved the immunity of the local surroundings. Then, the angiogenic peptides were also released through irradiation and they promoted angiogenesis. Additionally, the transported  could decrease the local glucose levels and spontaneously regress once the diabetic ischemic ulcers had healed.  combined with a functional polypeptide hydrogel may be a novel strategy for diabetic ischemic ulcer treatment.

An inflammatory memory and angiogenic self-assembling nanofiber hydrogel scaffold seeded with  to accelerate the healing of diabetic ischemic ulcers.

Despite the unprecedented success of immune checkpoint inhibitors (ICIs) as anti-cancer therapy, it remains a prevailing clinical need to identify additional mechanisms underlying ICI therapeutic efficacy and potential drug resistance. Here, using lineage tracking in cancer patients and tumor-bearing mice, we demonstrate that erythroid progenitor cells lose their developmental potential and switch to the myeloid lineage. Single-cell transcriptome analyses reveal that, notwithstanding quantitative differences in erythroid gene expression, erythroid differentiated myeloid cells (EDMCs) are transcriptionally indistinguishable from their myeloid-originated counterparts. EDMCs possess multifaceted machinery to curtail T cell-mediated anti-tumor responses. Consequently, EDMC content within tumor tissues is negatively associated with T cell inflammation for the majority of solid cancers; moreover, EDMC enrichment, in accordance with anemia manifestation, is predictive of poor prognosis in various cohorts of patients undergoing ICI therapy. Together, our findings reveal a feedforward mechanism by which tumors exploit anemia-triggered erythropoiesis for myeloid transdifferentiation and immunosuppression.

Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy.

Cytotoxic CD8 T cells are the main focus of efforts to understand anti-tumor immunity and immunotherapy. The adoptive transfer of tumor-reactive cytotoxic CD8 T lymphocytes expanded and differentiated  has long been considered the primary strategy in adaptive anti-tumor immunity, however, the majority of the transferred tumor antigen-specific CD8 T cells differentiated into CD39CD69 exhausted progenies, limiting its effects in repressing tumor growth. Contrarily, less attention has been addressed to the role of CD4 T cells during tumorigenesis. Using a mouse model of metastatic melanoma, we found that transferring tumor-specific CD4 T cells into recipients induces substantial regression of the established metastatic tumors. Notably,  activated CD4 T cells developed into cytotoxic CD4 T cells  and get exhausted gradually. The blockade of PD-L1 signaling resulted in an expansion of tumor specific CD4 T cells, which could better control the established metastatic melanoma. Moreover, the tumor-specific memory CD4 T cell can prevent mice from tumor metastasis, and the tumor-specific effector CD4 T cells can also mitigate the established metastatic tumor. Overall, our findings suggest a novel mechanism of CD4 T cells in curtailing tumor metastasis and confirm their therapeutic role in combination with PD-L1 blockade in cancer immunotherapy. Hence, a better understanding of cytotoxic CD4 T cell-mediated tumor regression could provide an alternative choice for patients exhibiting suboptimal or no response to CD8 T cell-based immunotherapies.

Article	Year
A novel dressing seeded with embryonic artery CD133 cells and loaded with the Sirt1 agonist SRT1720 accelerates the healing of diabetic ischemic ulcers. Experimental and therapeutic medicine\| PubMed ID: 29904408	2018
Letter to Editor: Association Between Postoperative Liver Dysfunction and Blood-Derived MicroRNA Signatures. Hepatology (Baltimore, Md.)\| PubMed ID: 31081219	2019
PUM1 knockdown prevents tumor progression by activating the PERK/eIF2/ATF4 signaling pathway in pancreatic adenocarcinoma cells. Cell death & disease\| PubMed ID: 31395860	2019
Effect of Comorbidity on Outcomes of Patients with Advanced Non-Small Cell Lung Cancer Undergoing Anti-PD1 Immunotherapy. Medical science monitor : international medical journal of experimental and clinical research\| PubMed ID: 32893263	2020
Human Positive Coactivator 4 Affects the Progression and Prognosis of Pancreatic Ductal Adenocarcinoma via the mTOR/P70s6k Signaling Pathway. OncoTargets and therapy\| PubMed ID: 33273827	2020
An inflammatory memory and angiogenic self-assembling nanofiber hydrogel scaffold seeded with to accelerate the healing of diabetic ischemic ulcers. RSC advances\| PubMed ID: 35539240	2018
Tumor-induced erythroid precursor-differentiated myeloid cells mediate immunosuppression and curtail anti-PD-1/PD-L1 treatment efficacy. Cancer cell\| PubMed ID: 35594863	2022
Tumor-Specific CD4 T Cells Restrain Established Metastatic Melanoma by Developing Into Cytotoxic CD4 T Cells. Frontiers in immunology\| PubMed ID: 35784297	2022
Tumor-specific memory CD8 T cells are strictly resident in draining lymph nodes during tumorigenesis. Cellular & molecular immunology\| PubMed ID: 36859455	2023
Author Correction: Tumor-specific memory CD8 T cells are strictly resident in draining lymph nodes during tumorigenesis. Cellular & molecular immunology\| PubMed ID: 37225839	2023
Comment On: Prospective Phase II Trials Validate the Effect of Neoadjuvant Chemotherapy on Pattern of Recurrence in Pancreatic Adenocarcinoma. Annals of surgery open : perspectives of surgical history, education, and clinical approaches\| PubMed ID: 37601477	2023

Xingxing Su

Biography

JoVE Journal Publications

Other Publications