Recent research is shedding light on the crucial role of B cells in the fight against cancer, opening exciting new avenues for therapeutic development, according to Stefano Gullà, Chief Scientific Officer at Kling Biotherapeutics. 

Cancer immunotherapies have been raising the bar for standard of care in oncology for more than a decade but equally, their drawbacks are well known, with low response rates and tough side-effects. 

There’s a need for new therapies that could be used either in combination with drugs such as checkpoint inhibitors, or that represent a significant improvement in safety and efficacy. 

The drugs could either work directly on tumours or amplify the immune response produced by immunotherapy drugs. 

By removing barriers in the tumour microenvironment (TME) that block the influx of cancer-killing T cells, scientists hope to make the effects of immunotherapy drugs more predictable by improving response rates and efficacy. 

One avenue of research is tumour-infiltrating B cells, which may be found organised into lymph-node-like structures in tumours that can secrete antibodies recognising tumour-associated antigens. This allows them to produce a local and sustained immune response against tumours. 

 Here’s why B cells, and in particular tumour associated B cells, deserve a closer look: 

  • B cells are more than just antibody factories: These immune cells actively participate in a complex interplay within the tumour microenvironment, contributing to both anti-tumour immunity and immune tolerance.  
  • B cells can guide us to new targets: By analysing the antibodies produced by tumour-infiltrating B cells and studying their clonal expansion, researchers can identify novel tumour-associated antigens (TAAs). These TAAs may be missed by traditional methods, and those specifically targeted by B cells associated with favourable prognosis hold special promise for therapeutic development.  
  • B cell-mediated antibody discovery: This research is directly revealing new therapeutic antibodies, offering a proven path to harnessing the power of the immune system to fight cancer. 

Three recent articles in BMJ, International Journal of Cancer, and Cell have highlighted the importance of looking into tumour associated B cells1-3

All three articles emphasise the growing recognition of B cells’ importance in fighting cancer. B cells are not just passive bystanders but actively contribute to the establishment of an organised immune response.  

This includes mechanisms such as antibody-dependent cellular cytotoxicity, promoting T cell activation, and contributing to long-term immune memory. B cells are crucial players in anti-tumour immunity and are associated with improved outcomes, especially in combination with T cells.  

The studies highlight a strong correlation between the presence of B cells (infiltrating tumours or in specific subsets), particularly when accompanied by a robust T cell response, and a more favourable prognosis for cancer patients. This is seen across a range of cancers, including melanoma, renal cell carcinoma, and ovarian cancer.  

The research shows that B cells are not a single entity but encompass diverse populations, each with specific roles and markers. This complexity is highlighted by the presence of various subtypes, such as those enriched for antigen presentation, those involved in antibody production, and those with regulatory functions. B cells are not just uniform, but heterogeneous and are involved in both anti-tumour immunity and immune tolerance. While B cells play a significant role in enhancing anti-tumour responses, they can also contribute to immune tolerance, potentially hindering the effectiveness of immunotherapy. The articles point to polyreactive antibodies, regulatory B cell subsets (Bregs), and specific B cell checkpoints like TIM-1 as potential mechanisms contributing to immune tolerance. 

The studies highlight the impact of the TME on B cell behaviour. This includes factors like the presence of tertiary lymphoid structures (TLSs), the cytokine milieu, and the interplay with other immune cell populations like T cells and macrophages. The TME can drive B cell activation, differentiation, and even the generation of specific subtypes.  

What therapeutic insights can be directly derived from tumour infiltrating B cells? 

1: New tumour-associated antigens: 

B cells as sentinels: B cells are uniquely positioned to recognise tumour-specific antigens. They encounter these antigens in the tumour microenvironment and initiate a humoral immune response, leading to the production of antibodies that target TAAs. 

Clonal expansion and BCR repertoire analysis: Analysing the BCR repertoire of tumour-infiltrating B cells can identify the specific antigens recognised by the antibodies produced by these cells. This analysis, particularly focusing on clonal expansion, can reveal novel TAAs that may be missed by traditional methods. 

Identifying TAAs associated with favourable prognosis: TAAs that are targeted by B cells associated with a better prognosis in patients may hold special promise as therapeutic targets. For example, if a specific TAA is targeted by B cells within TLS, and the presence of TLS is linked to better outcomes, this TAA could be prioritised for therapeutic development. 

2: New therapeutic antibodies 

B cell-mediated antibody discovery: Studying the antibodies produced by tumour-infiltrating B cells can provide a direct path to developing new therapeutic antibodies. These antibodies have a proven track record of effectiveness in treating cancer, as seen with current antibody-based therapies.  

Antibody engineering and optimisation: Once a new TAA has been identified, antibody engineering techniques can be used to optimise the newly discovered antibodies for better efficacy, specificity, and safety. This includes creating humanized antibodies, bispecific antibodies, and even antibodies that can engage different immune effector cells. 

3: B cell-specific therapies 

As B cell checkpoints and signalling pathways become better understood, therapies that specifically target B cells or their interaction with the tumour microenvironment can be developed. This could include blocking inhibitory checkpoints on B cells to enhance their anti–tumour activity or targeting B cell-specific molecules that promote tumour growth. 

Understanding the reactivity of B cells within tumours represents a powerful tool for discovering novel TAAs and developing new therapeutic antibodies. By leveraging the insights from B cell research, researchers can accelerate the development of more effective and targeted cancer therapies, ultimately improving patient outcomes. 

References

1:DOI:10.1136/jitc-2023-008636 

2: DOI: 10.1002/ijc.35149

3: DOI:10.1016/j.cell.2024.06.038