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Adoptive cell therapy (ACT) has revolutionized the treatment of patients with cancer. The success of ACT depends largely on transferred T cell status, particularly their less-differentiated state with stem cell-like properties, which enhances ACT effectiveness. Stem cell-like memory T (TSCM) cells exhibit continuous self-renewal and multilineage differentiation similar to pluripotent stem cells. TSCM cells are promising candidates for cancer immunotherapies, whereas maintenance of a more stem-cell-like state before transfer is challenging. Here, we established a highly efficient protocol for generating CD8+ TSCM cells from peripheral blood mononuclear cells (PBMCs). The process involved activating PBMCs using anti-CD3 monoclonal antibody and RetroNectin, followed by a transient-resting culture period (24 h) and subsequent long-term expansion in vitro with interlukien-2. We report that this transient-resting culture after activation preserves CD8+ T cells in a stem memory phenotype (CD95+ CD45RA+ CCR7+) compared to the conventional culture method. Further, this approach reduces the expression of T cell immunoglobulin mucin-3, an exhaustion marker, and increases the expression of T cell factor-1, a master regulator of stemness even after long-term culture compared to the conventional culture method. In conclusion, our study presents a simplified and cost-effective method for generating and expanding CD8+ TSCM cells ex vivo. This approach streamlines the optimization of cancer immunotherapy using ACT.

Abstract Background This study evaluated the efficacy and safety of low‐dose anlotinib combined with immune checkpoint inhibitors as second‐line or later treatment for extensive‐stage small cell lung cancer (ES‐SCLC). Methods The study included 42 patients with ES‐SCLC who were treated with low‐dose anlotinib combined with programmed cell death protein 1/programmed cell death‐ligand 1 inhibitors at Henan Cancer Hospital between March 2019 and August 2022. We retrospectively analyzed the efficacy and safety data for these patients. Indicators assessed included progression‐free survival (PFS), overall survival (OS), the overall response rate (ORR), the disease control rate (DCR), and adverse events (AEs). Prognostic factors were identified in univariate and multivariate analyses. Results Median PFS was 11.0 months (95% CI: 7.868–14.132) and median OS was 17.3 months (95% CI: 11.517–23.083). The ORR was 28.5% and the DCR was 95.2%. Treatment‐related AEs were noted in 27 patients (64.3%), the most common of which was thyroid dysfunction (26.2%). Grade 3/4 treatment‐related AEs were observed in two patients (4.8%). Conclusions A combination of low‐dose anlotinib and immune checkpoint inhibitors as second‐line or later treatment for ES‐SCLC may achieve longer PFS and OS and have manageable AEs.

Background: Although the use of anti-PD-1 antibodies has fundamentally changed traditional cancer treatment, most patients are resistant to anti-PD-1 treatment. Glucocorticoids (GCs) play an important role in tumorigenesis and tumor progression, but the role of endogenous GCs in resistance to anti-PD-1 antibody therapy remains unclear. Methods: Single cell-derived cell lines (SCDCLs) were generated from a colorectal cancer cell line (CT26) using limiting dilution. We analyzed tumor tissues from anti-PD-1 antibody-treated and untreated mice inoculated with SCDCLs via transcriptome sequencing and flow cytometry to detect pathway activity and immune cell composition changes in the tumor microenvironment. Results: Five SCDCLs were inoculated into wild-type BALB/c mice (all tumorigenic). Single-cell clone (SCC)-2 exhibited the slowest growth rates both in vivo and in vitro compared to other single-cell clones, and better long-term survival than SCC1 and CT26. Flow cytometry showed that SCC2 tumor-bearing mice exhibited significantly higher infiltration of T cells within the tumor tissue, and higher expression of PD-1 on these T cells than the other groups in vivo. However, the SCC2 group showed no response to anti-PD-1 therapy. Transcriptome analysis revealed that the SCC2 group exhibited increased expression of genes related to GC (Hsd11b1, Sgk3, Tgfbr2, and Il7r) compared to SCC2-anti-PD-1 treated tumors. Conclusions: GC pathway activation is related to resistance to anti-PD-1 therapy.

Intestinal flora affects the maturation of the host immune system, serves as a biomarker and efficacy predictor in the immunotherapy of several cancers, and has an important role in the development of colorectal cancer (CRC). Anti-PD-1/PD-L1 antibodies have shown satisfactory results in MSI-H/dMMR CRC but performed poorly in patients with MSS/pMMR CRC. In recent years an increasing number of studies have shown that intestinal flora has an important impact on anti-PD-1/PD-L1 antibody efficacy in CRC patients. Preclinical and clinical evidence have suggested that anti-PD-1/PD-L1 antibody efficacy can be improved by altering the composition of the intestinal flora in CRC. Herein, we summarize the studies related to the influence of intestinal flora on anti-PD-1/PD-L1 antibody efficacy in CRC and discuss the potential underlying mechanism(s). We have focused on the impact of the intestinal flora on the efficacy and safety of anti-PD-1/PD-L1 antibodies in CRC and how to better utilize the intestinal flora as an adjuvant to improve the efficacy of anti-PD-1/PD-L1 antibodies. In addition, we have provided a basis for the potential of the intestinal flora as a new treatment modality and indicator for determining patient prognosis.

Abstract Background Although the concept of declined immune function associated with cancer has been accepted extensively, real-world clinical studies focusing on analysis of the peripheral blood immune changes underlying ageing, immunity and cancer are scarce. Methods In this case-control study, we retrospectively analysed 1375 cancer patients and enrolled 275 age and gender matched healthy individuals. Flow cytometry was conducted to assess the immune changes. Further analysis was examined by SPSS 17.0 and GraphPad Prism 9 software. Results Cancer patients showed obviously decreased CD3+ T, CD3+CD4+ Th, CD3+CD8+ CTL, CD19+ B, CD16+CD56+ NK cell counts and lower percentage of PD-1 (programmed cell death protein-1, PD-1) positive cells than healthy control (P

Chemokines are a class of small cytokines or signaling proteins that are secreted by cells. Owing to their ability to induce directional chemotaxis of nearby responding cells, they are called chemotactic cytokines. Chemokines and chemokine receptors have now been shown to influence many cellular functions, including survival, adhesion, invasion, and proliferation, and regulate chemokine levels. Most malignant tumors express one or more chemokine receptors. The CXC subgroup of chemokine receptors, CXCR3, is mainly expressed on the surface of activated T cells, B cells, and natural killer cells, and plays an essential role in infection, autoimmune diseases, and tumor immunity by binding to specific receptors on target cell membranes to induce targeted migration and immune responses. It is vital to treat infections, autoimmune diseases, and tumors. CXCR3 and its ligands, CXCL9, CXCL10, and CXCL11, are closely associated with the development and progression of many tumors. With the elucidation of its mechanism of action, CXCR3 is expected to become a new indicator for evaluating the prognosis of patients with tumors and a new target for clinical tumor immunotherapy. This article reviews the significance and mechanism of action of the chemokine receptor CXCR3 and its specific ligands in tumor development.

Despite recent progress in treating advanced non-small cell lung cancer, clinical intervention in extensive-stage small-cell lung cancer (ES-SCLC) remains stagnant. The purpose of this study was to evaluate the clinical efficacy of cytokine-induced killer (CIK) cells combined with cytotoxic chemotherapy, followed by anti-programmed death 1 antibody (sintilimab) maintenance, in ES-SCLC patients. To explore a new method for safe treatment of ES-SCLC patients, thirteen ES-SCLC patients were enrolled between June 2019 and December 2021. All patients received first-line chemotherapy (etoposide plus platinum) combined with CIK cell therapy. Patients who reached a stable disease state or responded well to treatment received sintilimab maintenance treatment. The primary objective of this study was to determine the median overall survival (OS); the secondary objective was to assess the objective response rate (ORR), progression-free survival 1 and 2 (PFS1 was defined as the duration from the signing of informed consent to the date of tumor progression, or death, or the last follow-up. PFS2 was defined as the duration from the first day of sintilimab treatment to the date of tumor progression, death, or the last follow-up.), and adverse reactions. At a 24.1-month follow-up, the median OS was 11.8 (95% confidence interval [CI]: 10.6–13.0) months, median PFS1 was 5.5 (95% CI: 5.0–6.0) months, and the median PFS2 was 2.3 (95% CI: 0.5–4.1) months. The ORR was 76.9% (10/13), the disease control rate was 100% (13/13), and the 20-month survival rate was 41.7%. Eight participants exhibited grade 3 or 4 adverse events after combination therapy. During maintenance treatment with sintilimab, level 3 adverse events occurred in 1 patient (1/9). In conclusion, adding CIK cells to standard chemotherapy regimens, followed by maintenance therapy with sintilimab, may represent a new safe and effective treatment strategy.Clinical trial registrationClinicalTrials.gov (NCT03983759)

Background and ObjectiveThe results of the CheckMate 025 trial established the status of nivolumab in the second-line treatment of metastatic renal cell carcinoma (mRCC), with an objective response rate (ORR) of 25% and a complete response (CR) rate of 1%. Thus, the efficacy of anti-programmed death (PD)-1 antibodies in the second-line treatment of mRCC requires improvement. The purpose of this study was to explore the clinical efficacy and safety of anti-PD-1 agents combined with cytokine-induced killer (CIK) cell therapy for refractory mRCC.Patients and MethodsPatients with mRCC refractory to previous targeted therapy were included in this study. All patients received anti-PD-1 plus CIK cell therapy. The ORR and CR rate, progression-free survival (PFS), overall survival (OS), and safety were assessed.ResultsCR was observed in seven of the 29 patients, and partial response was observed in five patients. The ORR was 41.4% and the median PFS was 15.0 months. Up to the last follow-up, 15 patients died with an average survival time of 37 months. Among the patients who achieved a CR, one experienced cerebellar metastasis 18.8 months after discontinuation, but achieved CR again after localized gamma knife and 1-month axitinib treatment. This regimen was tolerated well and there was no treatment-related death.ConclusionsCombination therapy with anti-PD-1 and CIK cell therapy is safe and effective in patients with mRCC refractory to previous targeted therapy. The high CR rate and long disease-free survival even after long-term discontinued therapy suggest that this combination treatment may represent a potential curative regimen for this type of malignancy.

Abstract Background As a novel type of isothiocyanate derived from radish seeds from cruciferous vegetables, sulforaphene (SFE, 4-methylsufinyl-3-butenyl isothiocyanate) has various important biological effects, such as anti-oxidative and anti-bacterial effects. Recently, sulforaphene has attracted increasing attention for its anti-tumor effects and its ability to suppress the development of multiple tumors through different regulatory mechanisms. However, it has not yet been widely investigated for the treatment of esophageal cancer. Methods We observed an increased apoptosis in esophageal cancer cells on sulforaphene treatment through flow cytometry (FCM) analysis and transmission electron microscopy (TEM). Through mass spectrometry (MS) analysis, we further detected global changes in the proteomes and phosphoproteomes of esophageal cancer cells on sulforaphene treatment. The molecular mechanism of sulforaphene was verified by western blot,the effect and mechanism of SFE on esophageal cancer was further verified by patient-derived xenograft mouse model. Results We identified multiple cellular processes that were changed after sulforaphene treatment by proteomics. We found that sulforaphene could repress the phosphorylation of CREB through MSK2, leading to suppression of Bcl-2 and further promoted cell apoptosis. Additionally, we confirmed that sulforaphene induces tumor cell apoptosis in mice. Interestingly, we also observed the obvious inhibition of cell migration and invasion caused by sulforaphene treatment by inhibiting the expression of cadherin, indicating the complex effects of sulforaphene on the development of esophageal cancer. Conclusions Our data demonstrated that sulforaphene induced cell apoptosis and inhibits the invasion of esophageal cancer through a mechanism involving the inhibition of the MSK2–CREB–Bcl2 and cadherin pathway. Sulforaphene could therefore serve as a promising anti-tumor drug for the treatment of esophageal cancer.

Abstract Background Autologous tumor-infiltrating lymphocytes (Tils) immunotherapy is a promising treatment in patients with advanced hepatocellular cancer. Although Tils treatment has shown great promise, their persistence and the efficacy after adoptive-transfer are insufficient and remain a challenge. Studies have demonstrated that IL-15 and Akt inhibitor can regulate T cell differentiation and memory. Here, we constructed S-15 (Super human IL-15), a fusion protein consisting of human IL-15, the sushi domain of the IL-15 receptor α chain and human IgG-Fc. Herein we compared the effects of S-15 with IL-2 or in combination with Akti on the expansion and activation of Tils. Methods Hepatocellular cancer tissues were obtained from 6 patients, Tils were expanded using IL-2, IL-2/S-15, IL-2/Akti or in combination IL-2/S-15/Akti. At day 10, anti-CD3 antibody was added to the culture media and expanded to day 25. The composition, exhaustion and T-cell differentiation markers (CD45RA/CCR7) were analyzed by flow cytometry. Results We found that IL-2/S-15/Akti expanded Tils and showed the highest percentage of central memory CD45RA−CCR7+ phenotype prior to anti-CD3 antibody activation and after anti-CD3 antibody activation. T cells cultured with IL-2/S-15/Akti exhibited a mixture of CD4+, CD8+, and CD3+CD4−CD8− T cells; S-15 in combination with Akt inhibitor downregulated the expression of PD-1+Tim-3+ on Tils and decreased the Tregs in Tils. Additionally, the Tils expanded in the presence of the Akt inhibitor and S-15 showed enhanced antitumor activity as indicated by the increase in IFN-γ producing tumor infiltrating CD8+ T cells and without comprising the Tils expansion. Conclusion Our study elucidates that IL-2/S-15/Akti expanded Tils and represent a viable source for the cellular therapy for patients with hepatocellular cancer.

Background: The objective of this study was to assess the prognostic value of pretreatment platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-white blood cell ratio (LWR) of CRC patients who received neoadjuvant chemotherapy. Methods: We analyzed the peripheral blood routine parameters and other clinical data of 145 patients with colorectal cancer who had undergone neoadjuvant chemotherapy between January 2011 and February 2014. Pretreatment blood parameters of 145 patients were collected, and PLR, NLR, and LWR were calculated. The utility of PLR, NLR, and LWR in predicting treatment efficacy and patient survival was statistically evaluated using the chi-square test, log-rank test, Kaplan-Meier curves and logistic regression models, and Cox regression models. Results: Receiver operating characteristic curve showed that the best cutoff values of PLR, NLR, and LWR were 154.31, 3.01, and 0.22, respectively. In univariate analysis, tumor location ( P = 0.044), differentiation degree ( P = 0.001), lymph node metastasis ( P = 0.020), and high PLR ( P = 0.042) were significantly correlated with a lower overall response rate (ORR). In addition, clinical stage, lymph node metastasis, and high PLR were correlated with short OS ( P < 0.01) and DFS ( P < 0.01). Moreover, WBC count was correlated with a short OS. Multivariate analysis showed that tumor location ( P = 0.013), differentiation degree ( P = 0.001), and lymph node metastasis ( P = 0.033) were independent predictors of ORR. In addition, lymph node metastasis independently predicted a shorter OS ( P = 0.011). Lymph node metastasis ( P = 0.013) and high PLR ( P = 0.022) were independent prognostic factors for short DFS. Conclusions: For CRC patients who received NAC, clinical pathological stage and lymph node metastasis were correlated with lower ORR and survival, while a high PLR that may be of prognostic relevance in CRC patients receiving NAC.

Abstract Background T lymphocytes play an indispensably important role in clearing virus and tumor antigen. There is little knowledge about impacts of inhibitory molecules with cytokine on tumor-infiltrating CD4+ T-cells in the presence of gastric cancer (GC). This study investigated the distribution of tumor-infiltrating T-cells subset and the differentiation as well as inhibitory phenotype of T-cells from blood and tissues of GC patients. Materials and methods Patients with GC diagnosed on the basis of pre-operative staging and laparotomy findings were approached for enrollment between 2014 and 2015 at the Affiliated Cancer Hospital of Zhengzhou University, China. Phenotypic analysis based on isolation of tumor-infiltrating lymphocytes and intracellular IFN-γ staining assay is conducted. Statistical analysis is performed to show significance. Results The results showed that the percentage of CD4+ T-cells among CD3+ cells in tumors was significantly higher than that in the matched paraneoplastic tissue. CD4+ CD25high CD127low regulatory T-cells (Tregs), PD-1+, Tim-3+, and PD-1+ Tim-3+ cells were up-regulated on tumor infiltrating T-cells from patients with GC compared to their expressions on corresponding peripheral blood and peritumoral T-cells. Blockades of PD-1+ and Tim-3+ were effective in restoring tumor infiltrating T-cells’ production of interferon-gamma (IFN-γ). Combined PD-1+ and Tim-3+ inhibition had a synergistic effect on IFN-γ secretion by CD4+ T-cells. Conclusion The results suggested that the composition, inhibitors, and location of the immune infiltrate should be considered when evaluating antitumor immunotherapy. A new insight into the mechanisms underlying T cell dysfunction is provided.

Ribosomal protein L34 (RPL34) belongs to the L34E family of ribosomal proteins and contains a zinc finger motif. Aberrant expression of RPL34 has been reported in several human malignancies. However, the precise role and potential underlying mechanisms of RPL34 in human esophageal cancer remain largely unknown. Thus, the objective of this study was to investigate the role of RPL34 in esophageal cancer progression. Our results showed that the expression of RPL34 at both the mRNA and protein levels was frequently upregulated in esophageal cancer cell lines. Knockdown of RPL34 efficiently inhibited esophageal cancer cell proliferation, migration, and invasion in vitro. Mechanistically, knockdown of RPL34 significantly downregulated the protein expression level of p-PI3K and p-Akt in esophageal cancer cells. Finally, knockdown of RPL34 attenuated tumor growth in nude mice. In conclusion, our study revealed that RPL34 functions as an oncogene that modulates the proliferation and metastasis of esophageal cancer cells, in part, by the inactivation of the PI3K/Akt signaling pathway. Thus, these findings suggest that RPL34 may serve as a potential therapeutic target for the treatment of esophageal cancer. [ABSTRACT FROM AUTHOR]

Background: T lymphocytes play an indispensably important role in clearing virus and tumor antigen. There is little knowledge about impacts of inhibitory molecules with cytokine on tumor-infiltrating CD4+ T-cells in the presence of gastric cancer (GC). This study investigated the distribution of tumor-infiltrating T-cells subset and the differentiation as well as inhibitory phenotype of T-cells from blood and tissues of GC patients. Materials and methods: Patients with GC diagnosed on the basis of pre-operative staging and laparotomy findings were approached for enrollment between 2014 and 2015 at the Affiliated Cancer Hospital of Zhengzhou University, China. Phenotypic analysis based on isolation of tumor-infiltrating lymphocytes and intracellular IFN-γ staining assay is conducted. Statistical analysis is performed to show significance. Results: The results showed that the percentage of CD4+ T-cells among CD3+ cells in tumors was significantly higher than that in the matched paraneoplastic tissue. CD4+ CD25high CD127low regulatory T-cells (Tregs), PD-1+, Tim-3+ and PD-1+ Tim-3+ cells were up-regulated on tumor infiltrating T-cells from patients with GC compared to their expressions on corresponding peripheral blood and peritumoral T-cells. Blockades of PD-1+ and Tim-3+ were effective in restoring tumor infiltrating T-cell's production of interferon-gamma (IFN-γ). Combined PD-1+ and Tim-3+ inhibition had a synergistic effect on IFN-γ secretion by CD4+ T-cells. Conclusion: The results suggested that the composition, inhibitors and location of the immune infiltrate should be considered when evaluating antitumor immunotherapy. A new insight into the mechanisms underlying T cell dysfunction is provided. [ABSTRACT FROM AUTHOR]

The aim of the present study was to examine Ki-67 expression in tissue of luminal type breast cancer and to investigate the association between the Ki-67 expression level and clinicopathology of breast cancer. A total of 62 patients with breast cancer were included in the study group, whereas 30 patients undergoing a health check-up who were diagnosed with breast hyperplasia were included in the control group. Levels of Ki-67 expression in patients of the two groups were assessed using fluorescent quantitative polymerase chain reaction. The association between Ki-67 and the clinicopathology of the cancer was investigated by analyzing cancer cell proliferation and migration by reducing Ki-67 expression in the human MCF-7 cancer cell line. Compared with the controls, Ki-67 expression was significantly increased in the serum and cancer tissue of breast cancer patients (P<0.05). Ki-67 mRNA expression was significantly higher in cancer tissue than that in the corresponding paracancerous tissue of breast cancer (P<0.05). In addition, a high expression of Ki-67 was positively correlated with the clinical staging of tumor, tumor size and lymphatic metastasis of breast cancer, with statistical significance (P<0.05). In MCF-7 cells with a reduced Ki-67 expression, the proliferation activity and migration of breast cancer cells were significantly reduced (P<0.05). In conclusion, Ki-67 may be involved in promoting the genesis and development of breast cancer by affecting the proliferation and migration of cancer cells. [ABSTRACT FROM AUTHOR]