Pentoxifylline changes the balance of immune cell population in breast tumor-infiltrating lymphocytes.

Immunotherapy utilizing tumor-infiltrating lymphocytes (TILs) is a promising approach for cancer treatment. Pentoxifylline (PTXF), a xanthine derivative, exhibits antitumor properties. This study aimed to investigate the impact of PTXF on the phenotype and function of TILs and splenocytes in a triple-negative breast cancer (TNBC) mouse model. TNBC was subcutaneously induced in BALB/c mice, followed by nine intraperitoneal injections of 100 mg/kg PTXF. TILs were then isolated by enzymatic digestion of tumors and cocultured with 4T1 cells. The proportion of regulatory T cells (Tregs) and cytotoxic T cells in TILs and splenocytes was assessed using flow cytometry. Transforming growth factor (TGF)-ß and interferon (IFN)-γ production in TILs and splenocytes cultures was measured by ELISA. Relative expression of t-bet, foxp3, gata-3, and ror-γt in TILs and splenocytes was evaluated using real-time PCR. Tumor growth in PTXF-treated mice was significantly lower than that in the controls (P < 0.01). The frequency of regulatory and cytotoxic TILs in PTXF-treated mice was approximately half (P < 0.01) and twice (P < 0.05) that of the control group, respectively. The level of TGF-ß and IFN-γ in the supernatant of PTXF-treated TILs was decreased and increased, respectively (P < 0.05). The relative expression of t-bet and foxp3 in the PTXF-treated mice compared to controls was increased and decreased, respectively (P < 0.05). Changes in the immune cell balance were less significant in the spleen compared to the TILs. PTXF treatment could limit the tumor growth and modify the regulatory-to-cytotoxic TILs ratio, as well as cytokine balance of TILs, in favor of antitumor responses.

Prognostic Factors for the Long-Term Survival after Hematopoietic Stem Cell Transplantation in Patients with Hodgkin Lymphoma.

OBJECTIVES: This study investigated the possible prognostic factors for the long-term survival (Cure Rate) of Hodgkin Lymphoma patients who underwent HSCT. METHODS: This retrospective cohort study analyzed 116 Patients diagnosed with Hodgkin Lymphoma who received autologous hematopoietic stem cell transplantation (Auto-HSCT) between the years 2007 and 2014 and followed up until 2017. The information regarding patients' survival had been collected using phone calls, and their pre-transplant information was available in the archived documents. Prognostic effects were investigated using long-term survival models. RESULTS: Patients with obesity had five times higher odds of long-term survival (cure) than the others (P=0.06). Also, the recurrence experience after HSCT negatively impacted the curing potential by 78% (P=0.05). Also, with 32 years as the change point, patients younger than 32 had 76% fewer odds of surviving long-term (P=0.03), and Poor transfused stem cell dose of CD34+ (<0.16 × 106 cells/ml) reduced the odds of long-term survival by 92% (P=0.01). CONCLUSION: According to the statistical models used in this study, obesity can increase the curing potential of Hodgkin lymphoma after transplantation. Meanwhile, aging, poor transfused CD34+ cells, and recurrence after HSCT were associated with lower survival following HSCT.

Decrease of Tumor-infiltrating Regulatory T Cells Using Pentoxifylline: An Ex Vivo Analysis in Triple-negative Breast Cancer Mouse Model.

Triple-negative breast cancer (TNBC) is the most aggressive type of BC with the highest percentage of tumor-infiltrating lymphocytes (TILs). Hence, TIL therapy is considered a promising approach to target TNBC. Depletion of regulatory T cells (Tregs) in TILs can improve the antitumor function of TIL therapy. Pentoxifylline (PTXF) is a xanthine derivative that can modulate the nuclear factor kappa B (NF-κB) signaling and probably affect the Treg proportion in TILs. We aimed to evaluate the ex vivo effect of PTXF on the proportion of Treg cells in the TILs derived from a mouse model of TNBC. The 4T1 cells were inoculated subcutaneously to BALB/c mice to induce TNBC. TILs were isolated from tumor tissue by enzymatic digestion and cultured alone or with 4T1 cells for 24, 48, and 72 h in the presence of interleukin (IL)-2 and different concentrations of PTXF. The toxicity of PTXF and its effects on Tregs proportion as well as cytokine production was evaluated using MTT assay, flow cytometry, and ELISA, respectively. PTXF had no significant impact on the viability of TILs. Both 500 and 1000 mg/mL of PTXF decreased the proportion of Tregs in a dose-dependent manner. The level of interferon-g and tumor growth factor-b in TILs supernatant was increased and decreased, respectively. Our data suggest that ex vivo treatment of TILs with pentoxifylline could decrease the proportion of Tregs in the conventional IL-2-mediated TIL expansion and change the cytokine balance of TILs in favor of antitumor immune response.

Human platelet antigen 1-6, 9 and 15 in the Iranian population: An anthropological genetic analysis.

Human platelet antigens (HPAs) are membranous glycoproteins considered as alloantigens due to their polymorphisms. HPA-incompatibility in multiple pregnancies or blood transfusion can induce the development of alloantibodies leading to thrombocytopenia. The frequency of HPAs varies among populations, so that deep knowledge of HPA frequencies will help us to reduce those incompatibilities. Herein, we studied the allele and genotype frequencies of HPA1-6, HPA9, and HPA15 among the Iranians with intra- and inter-populations analyses on 36 worldwide populations with diverse ethnicities. The analysis shows that the HPA2 and HPA5 have the greatest differences in genotype distribution between the Iranians and other nations, although similar to other populations, the sole allele found in HPA4, 6, and 9 is "a". Despite other HPAs, the most frequent allele in HPA15 is "b", which is also abundant in HPA3. Hierarchical clustering indicates the highest degree of global similarity in HPA genotype frequency among Iranian, Argentinian, Brazilian, and German Turkish populations. Our findings can be applied to decrease the risk of alloimmunizations and platelet disorders, especially in neonates.

Plasma levels of norepinephrine and expression levels of ß2-adrenergic receptor gene correlate with the incidence of acute graft-versus-host disease.

Background: Acute graft-versus-host disease is a major complication in allogeneic hematopoietic stem-cell transplantation. Epinephrine and norepinephrine are stress hormones which affect many cells, including immune cells through interaction with adrenergic receptors, mainly ß2-adrenergic receptor. The immunomodulatory effects of epinephrine, norepinephrine, and signaling of the adrenergic receptor have been shown to decrease the probability of the acute graft-versus-host disease in animal models. The aim of our study was to investigate the possible correlations between the serum levels of epinephrine and norepinephrine and also leukocytic expression levels of ß2-adrenergic receptor with the incidence of acute graft-versus-host disease in patients undergoing allogeneic hematopoietic stem-cell transplantation. Methods: In this study, the plasma levels of epinephrine and norepinephrine and the leukocytic expression of ß2-adrenergic receptor gene were measured and compared in allogeneic hematopoietic stem-cell transplantation patients with and without acute graft-versus-host disease. Data were analyzed and illustrated using SPSS 19 and GraphPad Prism 6. The student T-test, Pearson, and Spearman's tests were performed and p<0.05 was considered as significant. Results: We showed that the plasma levels of norepinephrine and the relative amount of the mRNA of ß2-adrenergic receptor at 7 and 21 days after allogeneic hematopoietic stem-cell transplantation were significantly lower in patients with acute graft-versus-host disease than recipients without acute graft-versus-host disease. There were also negative correlations between the plasma levels of norepinephrine, leukocytic levels of the mRNA of ß2-adrenergic receptor, and the incidence of acute graft-versus-host disease. Conclusion: Our results suggest that stress hormones and their receptor might have a role in preventing acute graft-versus-host disease and could be promising factors in controlling the outcome of allogeneic hematopoietic stem-cell transplantation.