Biochemical controls: the role of B cells in cancer control (Introduction)

by David Turell , Friday, May 03, 2024, 18:35 (14 days ago) @ David Turell

B cells follow two patterns:

https://www.sciencemagazinedigital.org/sciencemagazine/library/item/03_may_2024/4192476...

"B cells are key players in adaptive immunity. In a typical response, B cells specific for an antigen become activated and proliferate in a transient structure called a germinal center (GC), where their B cell receptor (BCR) undergoes rounds of mutation, and clones with BCRs that bind antigen more robustly are selected. Selected GC B cells then become either memory cells, poised to respond to future challenge, or differentiate into antibody-secreting plasma cells. This process underpins both naturally acquired and vaccine-induced protection against infections. By contrast, the importance of B cells to the anticancer immune response has been largely overlooked and, where examined, has yielded contradictory findings. On page 524 of this issue, Ma et al. decode the functions of B cells infiltrating a variety of human tumors and show that it is the trajectory of the response, not the tumor type, that determines the impact of humoral immunity on cancer outcome.

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"An effective humoral response is associated with the formation of GCs in the follicles of secondary lymphoid organs, such as the lymph nodes, and the production of highly specific antibodies. However, B cells can also be generated by an extrafollicular (EF) pathway that directs the cells away from the GC and mutation-driven increases in BCR affinity. Tumors can also support an organized cluster of immune cells termed tertiary lymphoid structures (TLSs), which resemble those found in the secondary lymphoid organs. Although the most mature TLSs often correlate with a good patient prognosis, many tumors with B cell infiltrates display only disorganized or no TLSs, implying the existence of alternative differentiation pathways.

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"Ma et al. distinguished two maturation trajectories for tumor-infiltrating B cells. Besides the canonical GC pathway, which generates classical memory and high-affinity tumor-specific antibodies, they described a population of atypical memory (AtM) B cells present in immature TLSs that displayed the hallmarks of an EF response. These AtM cells expressed markers such as CD11c, FCRL4 (Fc receptor-like protein 4), and T-BET, features previously reported for mouse and human AtM B cells associated with aging, autoimmunity, and chronic infections. An EF origin of AtM B cells is in line with their association with immature TLSs and invites a “chicken and egg” question: Are the AtM B cells unable to participate in the GC reaction and thus limit the maturation of TLSs, or do immature TLSs drive the development of AtM B cells?

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"Although in most cancer types both potential B cell developmental trajectories coexist, some tumor types were strongly biased toward the GC (thyroid, gallbladder, and colon cancers) or EF (ovarian, renal, and bladder cancers) pathways. This preference suggests that the tumor microenvironment influences the decision between the two trajectories. Consistently, Ma et al. found that metabolic programming was a key feature that varied between GC and EF pathways, with the amino acid glutamine playing a prominent role in inducing AtM B cell differentiation. Glutamine has been identified as an immunomodulatory nutrient in immune cells, most notably in T cells and dendritic cells, and it is also an important nutrient for cancer cell growth. Furthermore, the glutamine-derived metabolite α-ketoglutarate is an epigenetic cofactor that mediates histone and DNA demethylation, linking metabolism to transcriptional networks and thus cellular identity. As such, glutamine-restriction could be an attractive therapeutic strategy to modulate B cell maturation pathways in cancer because it might simultaneously enhance the antitumor response and limit tumor growth. Future work on glutamine blockade in tumor models should consider examining the humoral response and AtM B cells to fully encompass the impact of this promising strategy.

"Collectively, the findings of Ma et al. reinforce the emerging but complex role of humoral immunity in cancer control. It now seems clear that it is the individual tumor microenvironment and the resulting makeup of the tumor-immune infiltrates, and not the tumor type per se, that affects whether B cells play a role in the cancer outcome. These findings provide a rationale for the development of a new class of immunotherapy that specifically promotes the most productive trajectory of tumor-specific B cell responses."

Comment: if your eyes glaze over reading all of this I'm not surprised. I've presented it to demonstrate how B cells function as master immune cells creating plasma cells and also an amazingly large library of antibodies for current and future use. My other point is to show how research gets deeply into the weeds showing processes in great molecular detail. From a theoretical standpoint, a natural development of these processes is impossible to conceive.