B cell clonality in cancer.

Carcinogenesis in the process of long-term co-evolution of tumor cells and immune environment essentially becomes possible due to incorrect decisions made, remembered, and reproduced by the immune system at the level of clonal populations of antigen-specific T- and B-lymphocytes. Tumor-immunity interaction determines the nature of such errors and, consequently, delineates the possible ways of successful immunotherapeutic intervention. It is generally recognized that tumor-infiltrating B cells (TIL-B) can play both pro-tumor and anti-tumor roles. However, the exact mechanisms that determine the contribution of clonal B cell lineages with different specificities and functions remain largely unclear. This is due to the variability of cancer types, the molecular heterogeneity of tumor cells, and, to a large extent, the individual pattern of each immune response. Further progress requires detailed investigation of the functional properties and phenotypes of clonally heterogeneous B cells in relation to their antigenic specificities, which determine the functionality of both effector B lymphocytes and immunoglobulins produced in the tumor environment. Based on a real understanding of the role of clonal antigen-specific populations of B lymphocytes in the tumor microenvironment, we need to learn how to develop new methods of targeted immunotherapy, as well as adapt existing treatment options to the specific needs of different patients and patient subgroups. In this review, we will cover B cells functional diversity and their multifaceted roles in the tumor environment.

Toolkit for mapping the clonal landscape of tumor-infiltrating B cells.

Our current understanding of whether B cell involvement in the tumor microenvironment benefits the patient or the tumor - in distinct cancers, subcohorts and individual patients - is quite limited. Both statements are probably true in most cases: certain clonal B cell populations contribute to the antitumor response, while others steer the immune response away from the desired mechanics. To step up to a new level of understanding and managing B cell behaviors in the tumor microenvironment, we need to rationally discern these roles, which are cumulatively defined by B cell clonal functional programs, specificities of their B cell receptors, specificities and isotypes of the antibodies they produce, and their spatial interactions within the tumor environment. Comprehensive analysis of these characteristics of clonal B cell populations is now becoming feasible with the development of a whole arsenal of advanced technical approaches, which include (1) methods of single-cell and spatial transcriptomics, genomics, and proteomics; (2) methods of massive identification of B cell specificities; (3) methods of deep error-free profiling of B cell receptor repertoires. Here we overview existing techniques, summarize their current application for B cells studies and propose promising future directions in advancing B cells exploration.

NMDA receptors in immune competent cells.

This review presents analysis of literature data indicating the presence of NMDA-type glutamate receptors in several types of immune competent cells such as thymocytes, lymphocytes, and neutrophils. The possible role of these receptors in the function of these cells is discussed. The interaction of the receptors with certain ligands circulating in the bloodstream and their role in modulation of immune function is described. It is suggested that homocysteine ​​acts as modulator of these receptors, and its toxicity is largely explained by hyperactivation of the NMDA-type glutamate receptors.

Effect of homocysteine on properties of neutrophils activated in vivo.

We have found that neutrophils begin to express NMDA receptors on their membranes after in vivo activation. These receptors are the target for action of homocysteine (HC). After incubation of activated neutrophils with HC, the degranulation process is stimulated and generation of reactive oxygen species is increased. We conclude that expression of NMDA receptors on neutrophil membrane makes neutrophils sensitive to HC. Thus, hyperhomocysteinemia may induce additional stimulation of immune competent cells.