Fang Wang

Here, we report that functional heterogeneity of macrophages in cancer could be determined by the nature of their precursors: monocytes (Mons) and monocytic myeloid-derived suppressor cells (M-MDSCs). Macrophages that are differentiated from M-MDSCs, but not from Mons, are immune suppressive, with a genomic profile matching that of M-MDSCs. Immune-suppressive activity of M-MDSC-derived macrophages is dependent on the persistent expression of S100A9 protein in these cells. S100A9 also promotes M2 polarization of macrophages. Tissue-resident- and Mon-derived macrophages lack expression of this protein. S100A9-dependent immune-suppressive activity of macrophages involves transcription factor C/EBPβ. The presence of S100A9-positive macrophages in tumor tissues is associated with shorter survival in patients with head and neck cancer and poor response to PD-1 antibody treatment in patients with metastatic melanoma. Thus, this study reveals the pathway of the development of immune-suppressive macrophages and suggests an approach to their selective targeting.

Understanding the role of different subtypes of tumor-infiltrating lymphocytes (TIL) in the immunosuppressive tumor microenvironment is essential for improving cancer treatment. Enriched γδ1 T-cell populations in TILs suppress T-cell responses and dendritic cell maturation in breast cancer, where their presence is correlated negatively with clinical outcomes. However, mechanism(s) that explain the increase in this class of regulatory T cells (γδ Treg) in patients with breast cancer have yet to be elucidated. In this study, we show that IP-10 secreted by breast cancer cells attracted γδ Tregs. Using neutralizing antibodies against chemokines secreted by breast cancer cells, we found that IP-10 was the only functional chemokine that causes γδ Tregs to migrate toward breast cancer cells. In a humanized NOD-scid IL-2Rγ(null) (NSG) mouse model, human breast cancer cells attracted γδ Tregs as revealed by a live cell imaging system. IP-10 neutralization in vivo inhibited migration and trafficking of γδ Tregs into breast tumor sites, enhancing tumor immunity mediated by tumor-specific T cells. Together, our studies show how γδ Tregs accumulate in breast tumors, providing a rationale for their immunologic targeting to relieve immunosuppression in the tumor microenvironment.

Cellular immunotherapy represented by CD19-directed chimeric antigen receptor T (CAR-T) cells has achieved great success in recent years. An increasing number of CAR-T therapies are being developed for cancer treatment, but the frequent and varied adverse events, such as "on-target, off-tumor toxicity", limit CAR-T application. Here, we identify the target antigen expression patterns of CAR therapies in 18 tissues and organs (peripheral blood mononuclear cells, bone marrow, lymph nodes, spleen, heart, ascending aortic tissue, trachea, lung, skin, kidney, bladder, esophagus, stomach, small intestine, rectum, liver, common bile duct, and pancreas) from healthy human samples. The atlas determines target antigens expressed on some normal cell types, which facilitates elucidating the cause of "on-target, off-tumor toxicity" in special tissues and organs by targeting some antigens, but not others. Moreover, we describe the target antigen expression patterns of B-lineage-derived malignant cells, acute myeloid leukemia (AML), and solid tumors. Overall, the present study indicates the pathogenesis of "on-target, off-tumor toxicity" during CAR therapies and provides guidance on taking preventive measures during CAR treatment.

Abstract Background BCMA CAR-T is highly effective for relapsed/refractory multiple myeloma(R/R-MM) and significantly improves the survival of patients. However, the short remission time and high relapse rate of MM patients treated with BCMA CAR-T remain bottlenecks that limit long-term survival. The immune microenvironment of the bone marrow (BM) in R/R-MM may be responsible for this. The present study aims to present an in-depth analysis of resistant mechanisms and to explore potential novel therapeutic targets for relapse of BCMA CAR-T treatment via single-cell RNA sequencing (scRNA-seq) of BM plasma cells and immune cells. Methods This study used 10X Genomic scRNA-seq to identify cell populations in R/R-MM CD45 + BM cells before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. Cell Ranger pipeline and CellChat were used to perform detailed analysis. Results We compared the heterogeneity of CD45 + BM cells before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. We found that the proportion of monocytes/macrophages increased, while the percentage of T cells decreased at relapse after BCMA CAR-T treatment. We then reclustered and analyzed the alterations in plasma cells, T cells, NK cells, DCs, neutrophils, and monocytes/macrophages in the BM microenvironment before BCMA CAR-T treatment and relapse after BCMA CAR-T treatment. We show here that the percentage of BCMA positive plasma cells increased at relapse after BCMA CAR-T cell therapy. Other targets such as CD38, CD24, SLAMF7, CD138, and GPRC5D were also found to be expressed in plasma cells of the R/R-MM patient at relapse after BCMA CAR-T cell therapy. Furthermore, exhausted T cells, TIGIT + NK cells, interferon-responsive DCs, and interferon-responsive neutrophils, increased in the R/R-MM patient at relapse after BCMA CAR-T cell treatment. Significantly, the proportion of IL1β hi Mφ, S100A9 hi Mφ, interferon-responsive Mφ, CD16 hi Mφ, MARCO hi Mφ, and S100A11 hi Mφ significantly increased in the R/R-MM patient at relapse after BCMA CAR-T cell therapy. Cell–cell communication analysis indicated that monocytes/macrophages, especially the MIF and APRIL signaling pathway are key players in R/R-MM patient at relapse after BCMA CAR-T cell therapy. Conclusion Taken together, our data extend the understanding of intrinsic and extrinsic relapse of BCMA CAR-T treatment in R/R-MM patient and the potential mechanisms involved in the alterations of antigens and the induced immunosuppressive microenvironment, which may provide a basis for the optimization of BCMA CAR-T strategies. Further studies should be performed to confirm these findings.

The aim of the present study was to evaluate the therapeutic effect of intra-articular hyaluronic acid (HA) in comparison to corticosteroids (CS) for knee osteoarthritis (OA). The data sources included PubMed, EMBASE, The Cochrane Central Register of Controlled Trials and hand searched reviews. Randomized controlled trials that reported the effects of intra-articular HA and CS in the treatment of knee OA were selected based on specific inclusion criteria. A meta-analysis was performed for the visual analog scale (VAS), Lequesne index, Knee Society Clinical Rating System (KSS), maximum flexion and adverse events of knee OA. Sensitivity analysis was also conducted to avoid bias. The seven eligible trials included 583 participants and the majority of the trials were of high quality. After one month, the mean difference in the VAS was 1.66 [95% confidence interval (CI); -0.90, 4.23), indicating equal efficacy for HA and CS. However, after three months, the mean difference was -12.58 (95% CI; -17.76, -7.40), while after six months, the difference was -9.01 (95% CI; -12.62, -5.40), favoring HA. For the additional indicators, including the Lequesne index, the KSS, maximum flexion and adverse events, no statistically significant differences were observed between the two treatment approaches for knee OA. Therefore, the results of the meta-analysis highlight a therapeutic trajectory for intra-articular HA in knee OA pain, as compared with CS, over six months post-intervention. After one month, the two approaches exhibited equal efficacy; however, in the long term, HA was found to have an enhanced effect. No statistically significant difference was observed in the adverse events caused by the two interventions. Further investigation and understanding into the trend observed in the present study may aid clinicians in the treatment of knee OA.