Biomedical subjects

Meixiao Long

Publications and source records attributed to Meixiao Long.

6 recordsLinked to original sources

PubMed2025

Repression of PRMT activities sensitize homologous recombination-proficient ovarian and breast cancer cells to PARP inhibitor treatment.

Therapeutic epigenetic modulation is currently being evaluated in the clinic to sensitize homologous recombination (HR)-proficient tumors to PARP inhibitors. To broaden its clinical applicability and identify more effective combination strategies, we conducted a drug screen combining PARP inhibitors with 74 well-characterized epigenetic modulators targeting five major classes of epigenetic enzymes. Notably, both type I PRMT inhibitors and PRMT5 inhibitors scored highly in combination efficacy and clinical prioritization. PRMT inhibition significantly enhanced PARP inhibitor-induced DNA damage in HR-proficient ovarian and breast cancer cells. Mechanistically, PRMT suppression downregulates DNA damage repair genes and BRCAness-associated pathways, while also modulating intrinsic innate immune responses within cancer cells. Integrative analysis of large-scale genomic and functional datasets from TCGA and DepMap further supports PRMT1, PRMT4, and PRMT5 as promising therapeutic targets in oncology. Importantly, dual inhibition of PRMT1 and PRMT5 synergistically sensitizes tumors to PARP inhibitors. Collectively, our findings provide strong rationale for the clinical development of PRMT and PARP inhibitor combinations in HR-proficient ovarian and breast cancers.

Journal Article↗

PubMed2006

Cutting edge: Paracrine, but not autocrine, IL-2 signaling is sustained during early antiviral CD4 T cell response.

IL-2 is expressed predominantly by activated T cells, and regulates T cell function by activating, via its receptor, the latent transcription factor STAT5. This signaling can occur in either a paracrine (between cells) or an autocrine (same cell) manner, although the kinetics by which these two signaling modes operate during in vivo T cell responses are unknown. In the current study, IL-2 expression and signaling in a clonotypic population of antiviral CD4+ T cells was analyzed by flow cytometry during the initial 24 h of priming. IL-2 expression and STAT5 activation peaked in parallel, but surprisingly, were almost completely mutually exclusive. Thus, only paracrine IL-2 signaling could be observed. As an additional indication of the efficiency of paracrine IL-2 signaling, polyclonal CD4+CD25+Foxp3+ regulatory T cells displayed detectable STAT5 activation under steady-state conditions, which was strongly enhanced by neighboring IL-2-expressing antiviral CD4 cells.

Adoptive Transfer↗

PubMed2006

T-bet down-modulation in tolerized Th1 effector CD4 cells confers a TCR-distal signaling defect that selectively impairs IFN-gamma expression.

When Th1 effector CD4 cells encounter tolerizing Ag in vivo, their capacity to express the effector cytokines IFN-gamma and TNF-alpha is lost more rapidly than noneffector functions such as IL-2 production and proliferation. To localize the relevant intracellular signaling defects, cytokine expression was compared following restimulation with Ag vs agents that bypass TCR-proximal signaling. IFN-gamma and TNF-alpha expression were both partially rescued when TCR-proximal signaling was bypassed, indicating that both TCR-proximal and -distal signaling defects impair the expression of these two effector cytokines. In contrast, bypassing TCR-proximal signaling fully rescued IL-2 expression. T-bet, a transcription and chromatin remodeling factor that is required to direct the differentiation of naive CD4 cells into IFN-gamma-expressing Th1 effectors, was partially down-modulated in tolerized Th1 effectors. Enforcing T-bet expression during tolerization selectively rescued the ability to express IFN-gamma, but not TNF-alpha. Conversely, expression of a dominant-negative T-bet in Th1 effectors selectively impaired the ability to express IFN-gamma, but not TNF-alpha. Analysis of histone acetylation at the IFN-gamma promoter further suggested that down-modulation of T-bet expression during Th1 effector CD4 cell tolerization does not impair IFN-gamma expression potential through alterations in chromatin structure.

Adoptive Transfer↗

PubMed2005

Androgen ablation mitigates tolerance to a prostate/prostate cancer-restricted antigen.

To understand the T cell response to prostate cancer, we created transgenic mice that express a model antigen in a prostate-restricted pattern and crossed these animals to TRAMP mice that develop spontaneous prostate cancer. Adoptive transfer of prostate-specific CD4 T cells shows that, in the absence of prostate cancer, the prostate gland is mostly ignored. Tumorigenesis allows T cell recognition of the prostate gland--but this recognition is tolerogenic, resulting in abortive proliferation and ultimately in hyporesponsiveness at the systemic level. Androgen ablation (the most common treatment for metastatic prostate cancer) was able to mitigate this tolerance--allowing prostate-specific T cells to expand and develop effector function after vaccination. These results suggest that immunotherapy for prostate cancer may be most efficacious when administered after androgen ablation.

Adoptive Transfer↗

PubMed2004

In vivo cyclophosphamide and IL-2 treatment impedes self-antigen-induced effector CD4 cell tolerization: implications for adoptive immunotherapy.

The development of T cell tolerance directed toward tumor-associated Ags can limit the repertoire of functional tumor-reactive T cells, thus impairing the ability of vaccines to elicit effective antitumor immunity. Adoptive immunotherapy strategies using ex vivo expanded tumor-reactive effector T cells can bypass this problem; however, the susceptibility of effector T cells to undergoing tolerization suggests that tolerance might also negatively impact adoptive immunotherapy. Nonetheless, adoptive immunotherapy strategies can be effective, particularly those utilizing the drug cyclophosphamide (CY) and/or exogenous IL-2. In the current study, we used a TCR-transgenic mouse adoptive transfer system to assess whether CY plus IL-2 treatment rescues effector CD4 cell function in the face of tolerizing Ag (i.e., cognate parenchymal self-Ag). CY plus IL-2 treatment not only enhances proliferation and accumulation of effector CD4 cells, but also preserves the ability of these cells to express the effector cytokine IFN-gamma (and to a lesser extent TNF-alpha) in proportion to the level of parenchymal self-Ag expression. When administered individually, CY but not IL-2 can markedly impede tolerization, although their combination is the most effective. Although effector CD4 cells in CY plus IL-2-treated self-Ag-expressing mice eventually succumb to tolerization, this delay results in an increased level of in situ IFN-gamma expression in cognate Ag-expressing parenchymal tissues as well as death via a mechanism that requires direct parenchymal Ag presentation. These results suggest that one potential mechanism by which CY and IL-2 augment adoptive immunotherapy strategies to treat cancer is by impeding the tolerization of tumor-reactive effector T cells.

Adjuvants, Immunologic↗

PubMed2003

Effector CD4 cell tolerization is mediated through functional inactivation and involves preferential impairment of TNF-alpha and IFN-gamma expression potentials.

It has recently been shown that effector/memory T cells can undergo peripheral tolerization in response to self-antigen. In the present study, we found that within 24h self-antigen profoundly impairs the ability of CD4 effectors to express TNF-alpha (and to a lesser extent IFN-gamma); however, several days of self-antigen exposure is required to impair non-effector functions such as IL-2 expression and proliferation. Since only half of the initial effector CD4 cell population expresses effector cytokines following brief antigenic stimulation, tolerization might have been mediated either through functional inactivation of effector-competent cells, or alternatively by the selective deletion of competent and expansion of non-competent cells. When briefly stimulated effectors were fractionated based on their expression of IFN-gamma, the IFN-gamma(-) sub-population was able to express IFN-gamma following secondary stimulation, indicating that all effector CD4 cells are functionally competent. Furthermore, both IFN-gamma(+) and IFN-gamma(-) sub-populations underwent tolerization in response to self-HA (although the former was slightly more prone to deletion at later time points). Thus, effector CD4 cell tolerization is mediated primarily through the functional inactivation of effector-competent cells.

Animals↗