Emerging Immune Checkpoints - BCL-2

B-cell lymphoma 2 (BCL-2) was initially identified as a critical regulator of apoptosis, the programmed cell death that maintains tissue homeostasis. Its primary role was considered anti-apoptotic, as it prevents cells from undergoing apoptosis, a process that is often exploited by cancer cells to survive and proliferate unchecked.

Fig.1. Bcl-2 family members regulate apoptosis.^1,2

However, recent research has unveiled a surprising twist in BCL-2's narrative—it also appears to have an immunosuppressive role, thereby emerging as a potential immune checkpoint.

BCL-2 and Immune Evasion

Cancer cells constantly devise new strategies to evade the immune system's surveillance. One such strategy involves hijacking the BCL-2 pathway. BCL-2 overexpression in cancer cells not only promotes their survival by resisting apoptosis but also exerts a suppressive effect on immune cells.

• Tumor-infiltrating lymphocytes (TILs), crucial players in the antitumor immune response, are often stymied by the presence of elevated BCL-2 levels in the tumor microenvironment. This suppressive action can render immune cells ineffective, allowing the tumor to thrive.
• BCL-2's association with regulatory T cells (Tregs), further strengthens its status as a potential immune checkpoint. BCL-2 is implicated in the survival and function of Tregs, raising intriguing questions about its role in immune regulation.

BCL-2 as a New Immune Checkpoint

Traditionally, BCL-2 has been recognized for its role in preventing apoptosis, or programmed cell death, in normal cells. However, recent studies have illuminated the discovery of BCL-2's involvement in immune regulation, which has opened up new avenues for research and therapeutic development.

BCL-2 hampers the immune response through various mechanisms, making it a formidable immune checkpoint.

• Suppression of Immune Recognition
  BCL-2 interferes with the release of cytochrome c from the mitochondria, thereby inhibiting the activation of caspases and the induction of apoptosis. This not only ensures the survival of cancer cells but also conceals the release of danger signals that would otherwise alert the immune system to the presence of a threat.
• Immune Cell Modulation
  BCL-2 influences the composition of the tumor microenvironment by promoting the survival of immunosuppressive cell populations such as Tregs and MDSCs. These cells further dampen the immune response, fostering an environment conducive to tumor progression.
• Resistance to Conventional Immunotherapies
  The upregulation of BCL-2 in cancer cells has been associated with resistance to traditional immune checkpoint inhibitors (ICIs) targeting PD-1 and CTLA-4. This suggests that BCL-2 acts as a protective shield for cancer cells when confronted with standard checkpoint blockade strategies.

Targeting BCL-2 in Cancer Immunotherapy

Researchers are now exploring strategies to harness the potential of BCL-2 inhibition in the fight against cancer.

• Small molecule inhibitors
• Combination therapies
• Gene editing techniques
• Monoclonal antibodies

In conclusion, the emergence of BCL-2 as a novel immune checkpoint represents a paradigm shift in cancer immunotherapy. Unlocking the potential of BCL-2 inhibition offers new hope in the battle against cancer.

At Creative Biolabs, we remain committed to exploring innovative strategies to target BCL-2 and elevate the prospects of successful cancer immunotherapy.

References

1. Adams, Clare M., et al. "Targeting the Bcl-2 family in B cell lymphoma." Frontiers in oncology 8 (2019): 636.
2. Under Open Access license CC BY 4.0, without modification.

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