Mechanically, adaptive immunity is well positioned to recognize and destroy tumor cells. It is the successful antigen-specific clonal immune response that is associated with the control of tumor growth and the response to immunotherapeutic intervention. However, only a portion of patients with limited tumor types respond to the available immunotherapeutics.

To a large extent, this could be attributed to the clonal populations of antigen-specific memory T- and B-lymphocytes that have once chosen and then reproduce inappropriate effector response in the tumor milieu. Such deleterious clonal decisions may include: 1) tumor-tolerant behavior; 2) promotion of immune responses that do not lead to tumor cells eradication, but compete with and suppress cytotoxic anti-tumor response; 3) supporting the inflammatory environment which is employed by tumor cells; 4) focusing on the tumor antigens that are poorly represented on the surface of tumor cells. Erroneous clonal decisions may occur and accumulate in the course of a long-term inflammation, by chance or as a result of bidirectional interaction between evolving tumor and immune system, where the former evolves to manipulate the latter.

Analysis of the clonal, antigen-specific, and phenotypic diversity of lymphocytes in a tumor environment can unveil the nature of adaptive immunity errors and delineate the most efficient anti-tumor functionalities and specifics, suggesting the keys to targeted and efficient cancer immunotherapy.

In this review, we focus on the B cell component of the tumor environment. Remaining in the background of the T-cell component in current research and clinics, B-lymphocytes nevertheless play important roles in the pro- and antitumor antigen-specific immune responses. Maturing towards plasma cells, they produce antibodies of different specificity and isotype-determined functionality. On the other hand, they represent an important component of cellular immunity, with B cell receptor (BCR) enabling both antigen-specific effector functions and focused antigen capturing for further presentation to helper and cytotoxic T cells.

Making sense of this tangled picture is challenging, and requires a whole arsenal of methods and approaches to unravel the phenotypic, functional, spatial, and antigen-specific landscape of B cells in the TME. Here we also attempt to cover and structure the diversity of these rapidly evolving tools.