With advancements in biology and medicine, our understanding of cancer and the autoimmune system has deepened, leading to significant breakthroughs in cancer treatment. The discovery of immune checkpoints, such as PD-1/PD-L1, and the emergence of immune checkpoint inhibitors in tumor immunotherapy have revolutionized cancer treatment and brought hope to cancer patients.
Tumor cells employ various mechanisms to evade the immune system, and immune checkpoints play a crucial role in this process, acting as "brakes" for immune cells, while tumor cells express high levels of ligands that bind to these "brakes" on their surface. The combination of the two effectively suppresses immune cell activity, enabling tumor cells to escape recognition and destruction. Immune checkpoint inhibitors are designed to release these "brakes" and restore immune responses for cancer therapy.
B cells, as essential immune cells, play a pivotal role in both innate and adaptive immunity. Different subsets of specialized B cells contribute to diverse functions ranging from antigen presentation to antibody production. Interestingly, B cells are also abundant in tumor-infiltrating leukocytes (TILs), particularly in melanoma. However, the role of B cells in antitumor immunity remains a topic of debate. Consequently, tumor immunotherapy has primarily focused on T cells and natural killer cells (NK cells) to impede tumor growth.
On June 21, 2023, a collaborative research paper by scientists from Harvard Medical School, the Boulder Institute, and Genentech was published in Nature, titled "B-cell-specific checkpoint molecules that regulate anti-tumour immunity".
The research team conducted a comprehensive investigation into the involvement of B cells in the fight against cancer. They identified a critical immune checkpoint, TIM-1, that is activated in B cells and explored how targeting this checkpoint could unlock the antitumor potential of T cells. By inhibiting TIM-1, which suppresses B cells, the researchers observed enhanced anti-tumor responses in CD8+ and CD4+ T cells, leading to suppressed tumor growth. These findings carry significant implications for cancer therapy.
Using high-throughput flow cytometry, bulk sequencing, and single-cell RNA sequencing, the team studied various B cell types during melanoma growth and monitored their gene expression profiles. The results unveiled a distinct subpopulation of B cells that exhibited substantial expansion over time in the draining lymph nodes of tumor-bearing mice.
This B cell subpopulation displayed high levels of TIM-1 protein, encoded by the Havcr1 gene. It also expressed co-repressor molecules such as PD-1, TIM-3, TIGIT, and LAG-3. Conditional deletion of these co-repressor molecules on B cells had minimal impact on tumor load, whereas deletion of the Havcr1 gene in B cells significantly impeded tumor growth and bolstered effector T cell responses.
The deletion of TIM-1 enhanced type 1 interferon (IFN-1) responses in B cells, resulting in heightened B cell activation, augmented antigen presentation, and enhanced costimulation. Consequently, this led to the expansion of tumor-specific effector T cells. Moreover, commercially available high-affinity anti-TIM-1 antibodies exhibited substantial inhibition of tumor growth.
In contrast to T cells, the mechanisms associated with specific B cell tumors remain unclear. Generally, an effective immune response against pathogens relies on synergistic actions through intracellular signaling cascades, wherein multiple signals initiate and regulate immune response activity.
This specific subpopulation of B cells expressing TIM-1 may serve as a health regulatory checkpoint for T cell activation, limiting excessive immune responses. This regulatory function might be unrelated to tumor growth, presenting a paradoxical situation where the immune system may not mount an aggressive attack against tumor cells.
B cell responses have been associated with positive outcomes in various cancers, facilitating cooperation between B and T cells within the tumor microenvironment. However, this study identifies TIM-1 as a critical immune checkpoint for B cell activation. TIM-1 influences the IFN-1 response of B cells, curbing their activation, antigen presentation, and costimulation. This highlights TIM-1 as a potential target to enhance B cell responses and promote antitumor immunity.