Participation of B cell in immunotherapy of cancer.

Even though their effector roles extend beyond conventional humoral immunity, B and plasma cells may exhibit antitumor effects through antibody-dependent cell cytotoxicity (ADCC) and activation of the complement cascade. Depending on whether they are positioned in immature or mature compartments termed tertiary lymphoid structures (TLS), which include T cells, B cells are believed to play numerous functions in modulating the immune system's capacity to destroy cancer cells. These formations represent a process of lymphoid neogenesis that takes place in peripheral tissues in response to prolonged exposure to inflammatory signals. Activated in the germinal centres of tertiary lymphoid structures, B cells may directly present tumor-associated antigens to T cells, make antibodies that enhance antigen presentation to T cells, or kill tumour cells, resulting in a favourable therapeutic effect. Immune complexes may also enhance inflammation, angiogenesis, and immunosuppression via the activation of macrophages and complement, resulting in detrimental effects. The functional variety of B-cell subsets includes professional antigen-presenting cells, regulatory cells, memory populations, and plasma cells that produce antibodies. Importantly, antibodies may independently generate innate immune responses and the cancer immunity cycle. B cells and B-cell-mediated antibody responses constitute the largely underestimated second arm of the adaptive immune system and unquestionably need more consideration in cancer. This article reviews the known roles of B lymphocytes in the tumour microenvironment, their contribution to anticancer activity of immunotherapies, and their significance in overall survival of cancer patients. In addition to producing antibodies, B cells regulate the immune system and serve as effective antigen-presenting cells.

Association of Wiskott-Aldrich syndrome protein (WASp) in epigenetic regulation of B cell differentiation in non-small-cell lung cancer (NSCLC).

Non-small-cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer which is the deadliest type of cancer for both men and women. Previous studies already showed that cell-intrinsic loss of WASp causes B cell tolerance and WASp deficiency in T helper (TH) cells is linked to negative effects on cytokine gene transcription necessary for TH1 differentiation. In the current study, we investigated the molecular mechanisms involved in WASp-mediated epigenetic regulation of B cell differentiation during NSCLC. Our ChIP-qPCR data suggest the less percentage enrichment of the B cell differentiating factors (Ikaros, Pax5, PU.1, BATF) and WASp across the WAS gene in the B cells of NSCLC patients in comparison with normal healthy donors and overexpression of WASp showed the reverse effects. WASp-depleted B cells while co-culturing with respective PBMCs isolated from normal healthy donors and NSCLC patients, we observed upregulation of TH2-, TH17-, and Treg-specific cytokines (IL4, ILI7A, IL10) & transcription factors (GATA3, RORC, FOXP3) and downregulation of TH1-specific cytokine (IFNγ) & transcription factor (TBX21). Our study showed that the overexpression of WASp resulted into upregulation of B cell differentiating factors, tumor suppressor protein (p53), histone methylation marker (H3K4me3) with concomitant downregulation of tumor-promoting factors (Notch 1, ß-Catenin, DNAPKcs) and histone deacetylation marker (HDAC2) and increase in percentage cytotoxicity of NSCLC-specific cells (A549). Successful overexpression of WASp not only helps in epigenetic regulation of B cell differentiation but also supports tumor suppression in NSCLC. Thus, WASp can be targeted for therapeutic intervention of NSCLC.

Epigenetic regulation of enhancer of zeste homolog 2 (EZH2) -Yin Yang 1 (YY1) axis in cancer.

In accordance with the World Health Organization, cancer is the second leading cause of death in patients. In recent years, the number of cancer patients has been growing, and the occurrence of cancer in people is becoming more common, primarily due to lifestyle factors. Yin Yang 1 (YY1) is a transcription factor that is widespread throughout. It is a zinc finger protein, falling under the GLI-Kruppel class. YY1 is known to regulate transcriptional activation and repression of various genes associated with different cellular processes such as DNA repair, autophagy, cell survival and apoptosis, and cell division. Meanwhile, EZH2 is a histone-lysine N-methyltransferase enzyme encoded by gene 7 in humans. Its main function involves catalyzing the addition of methyl groups to histone H3 at lysine 27 (H3K27me3), and it is involved in regulating CD8 + T cell fate and function. It is a subunit of a Polycomb repressor complex 2 (PRC2). The EZH2 gene encodes for an enzyme that is involved in histone methylation and transcriptional repression. It adds methyl groups to lysine 27 on histone H3 (H3K27me3) with the help of the cofactor S-adenosyl-L-methionine. In addition to its role in epigenetic regulation, EZH2 also acts as a regulator of CD8+ T cell fate and function. EZH2 has been implicated in T Cell Receptor (TCR) signaling via the regulation of actin polymerization. In fact, EZH2 is involved in numerous signaling pathways that lead to tumorigenesis. EZH2 is mutated in cancer and shows overexpression. Due to its mutation and overexpression, the cells that help combat cancer are suppressed and carcinogenicity is promoted. The association of EZH2 and YY1 poses an intriguing mechanism in relation to cancer.

Depletion of enhancer zeste homolog 2 (EZH2) directs transcription factors associated with T cell differentiation through epigenetic regulation of Yin Yang 1(YY1) in combating non-small cell lung cancer (NSCLC).

Non-Small Cell Lung Cancer (NSCLC) is the leading cause of death in all countries alike. In the current study, we have found out that Histone H3Lys4trimethylation is abnormal on YY1 in CD4+T Helper (TH) cells of NSCLC patients which is evident by Histone H3Lys27 trimethylation mediated via EZH2. We investigated the status of Yin Yang 1 (YY1) and the involvement of certain transcription factors that lead to tumorigenesis after depleting endogenous EZH2 in vitro by CRISPR/Cas9 in the CD4+TH1-or-TH2-polarized cells isolated initially as CD4+TH0 cells from the PBMC of the control subjects and patients suffering from NSCLC. After depletion of endogenous EZH2, RT-qPCR based mRNA expression analysis showed that there was an increase in the expression of TH1 specific genes and a decrease in the expression of TH2 specific genes in NSCLC patients CD4+TH cells. We can conclude that this group of NSCLC patients may have the tendency at least in vitro to elucidate adaptive/protective immunity through the depletion of endogenous EZH2 along with the reduction in the expression of YY1. Moreover, depletion of EZH2 not only suppressed the CD4+CD25+FOXP3+Regulatory T cells (Treg) but also it aided the generation of CD8+Cytotoxic T Lymphocytes (CTL) which were involved in killing of the NSCLC cells. Thus the transcription factors involved in EZH2 mediated T cell differentiation linked to malignancies offers us an appealing avenue of targeted therapeutic intervention for NSCLC.