Objective Checkpoint immunotherapy unleashes T-cell control of tumours but is suppressed by immunosuppressive myeloid cells. The transmembrane protein MS4A4A is selectively highly expressed in tumour-associated macrophages (TAMs). Here, we aimed to reveal the role of MS4A4A + TAMs in regulating the immune escape of tumour cells and to develop novel therapeutic strategies targeting TAMs to enhance the efficacy of immune checkpoint inhibitor (ICI) in colorectal cancer. Design The inhibitory effect of MS4A4A blockade alone or combined with ICI treatment on tumour growth was assessed using murine subcutaneous tumour or orthotopic transplanted models. The effect of MS4A4A blockade on the tumour immune microenvironment was assessed by flow cytometry and mass cytometry. RNA sequencing and western blot analysis were used to further explore the molecular mechanism by which MS4A4A promoted macrophages M2 polarisation. Results MS4A4A is selectively expressed by TAMs in different types of tumours, and was associated with adverse clinical outcome in patients with cancer. In vivo inhibition of MS4A4A and anti-MS4A4A monoclonal antibody treatment both curb tumour growth and improve the effect of ICI therapy. MS4A4A blockade treatment reshaped the tumour immune microenvironment, resulting in reducing the infiltration of M2-TAMs and exhausted T cells, and increasing the infiltration of effector CD8 + T cells. Anti-MS4A4A plus anti-programmed cell death protein 1 (PD-1) therapy remained effective in large, treatment-resistant tumours and could induce complete regression when further combined with radiotherapy. Mechanistically, MS4A4A promoted M2 polarisation of macrophages by activating PI3K/AKT pathway and JAK/STAT6 pathway. Conclusion Targeting MS4A4A could enhance the ICI efficacy and represent a new anticancer immunotherapy.
Background: Systemic sclerosis (scleroderma, SSc) is a rare complex connective tissue disease associated with high mortality and high morbidity 1 . Active SSc are typically treated with immunosuppressants, which may create a variety of severe side-effects, especially for long-term treatment 2 . As the pathogenesis of SSc is still a matter of debate, growing evidences have focused on the immune disorders 3 . However, the quantitative status of lymphocyte subsets in SSc patients are unclear and effects of immunomodulatory combination therapies (avoiding side-effects of conventional therapy) on the lymphocyte subsets are unknown. Objectives: To investigate the quantitative status of peripheral lymphocyte subpopulations and CD4+T subsets in SSc patients for the exploration of SSc pathogenesis and evaluate the effects of new immunomodulatory combination therapies on those cells. Methods: From July 2014 to December 2019, total 166 patients with SSc and 206 healthy controls (HCs) were enrolled in this study, in which, 79 follow-up patients received immunomodulatory drugs (IMiDs) such as low-dose interleukin-2, rapamycin, metformin, retinoic acid and coenzyme Q10. The absolute numbers of T, B, NK, CD4+T, CD8+T, Th1, Th2, Th17 and Tregs in peripheral blood of these subjects were detected by flow cytometry combined with standard absolute counting beads. Results: Patients with SSc had lower absolute counts of total T, NK, Th2, Th17 and Tregs as compared with those of HCs ( P <0.05) (Figure 1). After immunomodulatory combination treatments, there were increases in a various of peripheral lymphocyte subsets such as T, B and CD8+T ( P < 0.05). Moreover, the increased level of Tregs was much more dramatical than those of other lymphocyte subsets, resulting in the decrease ratios of Teffs/Tregs such as Th1/Tregs and Th2/Tregs and rebuilding immunologic equilibrium (Figure 2). Conclusion: This cross-sectional study clarified the abnormal status of lymphocyte subsets in SSc patients, suggesting lymphocyte subsets, especially Tregs, might be relevant and play a crucial role in the pathogenesis of SSc, thus providing a potential therapeutic target for SSc patients. Immunomodulatory combination therapies effectively increase the level of Tregs as well as other lymphocytes to some degree and maintain the immunologic equilibrium, which may help for SSc patients’ symptom remission. References: [1]Denton CP, Khanna D. Systemic sclerosis. Lancet 2017;390(10103):1685-99. doi: 10.1016/S0140-6736(17)30933-9 [published Online First: 2017/04/18] [2]Winthrop KL, Weinblatt ME, Bathon J, et al. Unmet need in rheumatology: reports from the Targeted Therapies meeting 2019. Ann Rheum Dis 2020;79(1):88-93. doi: 10.1136/annrheumdis-2019-216151 [published Online First: 2019/10/31] [3]Skaug B, Khanna D, Swindell WR, et al. Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile. Ann Rheum Dis 2019 doi: 10.1136/annrheumdis-2019-215894 [published Online First: 2019/11/27] Acknowledgments : None. Disclosure of Interests: None declared
Objective To observe the impact of srict glycemic control on cells induced by inflammatory cytokines which after cardiopulmonary bypass.Methods The non-diabetic patients undergoing cardiac surgery under cardiacpulmonary bypass in our department from 2006 to 2008 were selected and assigned to intensive therapy group(group A,n=32)and received strict glycemic contral after the initiation of surgery.And those who undergoing cardiac surgery but without strict glycemic control were assigned to routine therapy group(group B,n=32)as controls.The blood glucose in group A was maintained at 180-200 mg/dl,whereas the glucose in group B was at 70-150 mg/dl.The concentration of IL-6 and TNF-αwere measured after the surgery.Moreover,the time on ventilator,length of stay in ICU,length of postoperativehospital stay were recorded.Results There were no significant differences in general data between two groups.The concentration of IL-6 and TNF-αin group A was decreased,and there were significant differences between the two groups(both P0.05).Compared with group B,strict glycemic control markedly shorten the time on ventilator and length of postoperative hospital stay(both P0.05).Conclusion Strict glycemic control may significantly mitigate the systemic inflammatory response,and shorten the time on ventilator and length of postoperative hospital stay,leading to an improved prognosis.
Background: Rheumatoid arthritis (RA) is an aggressive immune-mediated joint disease with synovial inflammation and joint destruction characterized by abnormal immune responses to self-antigens 1 . An imbalance in pro- and anti-inflammatory lymphocyte subsets has been considered to contribute to the pathogenesis of RA 2 . However, the detailed lymphocyte statuses of RA patients are required clarified and the effect of immunomodulatory therapy on the lymphocyte subsets is unclear 3 . Objectives: To investigate the status of lymphocyte subsets in peripheral blood (PB) of RA patients at relatively large-sample size and the changes of them after our immune regulatory combination treatment. Methods: This cross-sectional study enrolled 3016 patients with RA who met the ACR’s revised RA diagnostic classification in 1987 as well as 206 healthy controls (HCs). Among these participations, 1415 patients have received the treatment of immunomodulatory drugs (IMiDs) such as low-dose interleukin-2, rapamycin, metformin, retinoic acid etc. Flow cytometry (FCM) was used to measure the levels of PB lymphocyte subgroups and CD4+T subsets in RA patients before and after the treatments and HCs. Data were expressed as mean ± standard deviation to the distribution. Independent-samples T test and paired-samples T test were applied. P value <0.05 were considered statistically significant. Results: C ompared with HCs, patients with RA had a lower absolute numbers of total T, CD8 + T, NK and Tregs ( P <0.05), decreased percentages of NK, Th1, Th2 and Th17 ( P <0.05), but higher ratios of Teffs/Tregs such as Th1/Tregs and Th17/Tregs (P<0.05), indicating a disturbance of immune systems (Figure 1). After receiving combined immunomodulatory therapy, the absolute numbers of T, B, CD4 + T, CD8 + T, NK, Th1, Th17 and Tregs were dramatically increased ( P <0.05) and the percentages of B, Th1, CD4 + T and Tregs were also increased ( P <0.05). Although these subsets increased globally, the ratio of Teffs/Tregs such as Th2/Tregs and Th17/Tregs tended to decrease, suggesting a rebalance of immune systems(Figure 2). Conclusion: Impaired peripheral lymphocytes especially insufficiency of Tregs might played an important role in pathogenesis of RA. Immunoregulatory combination therapies could promote the proliferation and functional recovery of Tregs in patients and help to alleviate disease activity. References: [1]Smolen JS, Aletaha D, McInnes IB. Rheumatoid arthritis. (1474-547X (Electronic)) [2]Kondo Y, Yokosawa M, Kaneko S, et al. Review: Transcriptional Regulation of CD4+ T Cell Differentiation in Experimentally Induced Arthritis and Rheumatoid Arthritis. (2326-5205 (Electronic)) [3]Fonseka CY, Rao DA, Raychaudhuri S. Leveraging blood and tissue CD4+ T cell heterogeneity at the single cell level to identify mechanisms of disease in rheumatoid arthritis. (1879-0372 (Electronic)) Acknowledgments: None. Disclosure of Interests: None declared
Abstract Disturbances in tumor cell metabolism reshape the tumor microenvironment (TME) and impair antitumor immunity, but the implicit mechanisms remain elusive. Here, we found that spermine synthase (SMS) was significantly upregulated in tumor cells, which correlated positively with immunosuppressive microenvironments and predicted poor survival in hepatocellular carcinoma (HCC) patients. Via “subcutaneous” and “orthotopic” HCC syngeneic mouse models and a series of in vitro coculture experiments, we identified elevated SMS level in HCC cells played a role in immune escape mainly through its metabolic product spermine, which induced tumor-associated macrophage (TAM) reprogramming and subsequently corresponded with a decreased antitumor functionality of CD8+ T cells. Mechanistically, we discovered that spermine reprogrammed TAM mainly by activating the PI3K-Akt-mTOR-S6K signaling pathway. Spermine inhibition in combination with immune checkpoint blockade effectively diminishes tumor burden in vivo. Our results expand the understanding of the critical role of metabolites in regulating cancer progression and anti-tumor immunity, and open new avenues for developing novel therapeutic strategies against HCC.
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