A global team has discovered a possible reason why some cancer patients undergoing a type of immunotherapy known as checkpoint inhibitors become more prone to typical infections.
A global team, co-led by the Garvan Institute of Medical Research, has discovered a potential reason why some cancer patients treated with immunotherapy known as checkpoint inhibitors show a higher vulnerability to frequent infections.
The results, published in the journal Immunity, offer new perspectives on immune responses and suggest a possible strategy to prevent this common side effect of cancer therapies.
“Checkpoint inhibitor therapies have transformed cancer care by enabling T cells to more effectively target and destroy tumors and cancer cells. However, these treatments come with side effects — notably, around 20% of patients on checkpoint inhibitors report a higher rate of infections, a detail that was not well understood until now,” explains Professor Stuart Tangye, co-senior author and Head of the Immunology and Immunodeficiency Lab at Garvan.
“Our research shows that although checkpoint inhibitors enhance the body’s ability to fight cancer, they may also weaken B cells, which are responsible for producing antibodies that protect against ordinary infections. This insight is a vital step in understanding and mitigating the treatment’s potential negative effects on the immune system.”
Advancements for immunotherapy
The research focused on the molecule PD-1, serving as a sort of ‘brake’ for the immune system to prevent T cells from becoming overly active. Checkpoint inhibitor therapies work by removing this molecular ‘brake’ to boost the immune system’s capacity to combat cancer.
This investigation was a collaboration with Rockefeller University in the USA and Kyoto University Graduate School of Medicine in Japan, analyzing the immune cells of patients with rare genetic mutations affecting PD-1 or its binding partner PD-L1 and using animal models lacking PD-1 signaling. They found that diminished or absent PD-1 activity may lead to a significant decrease in the variety and effectiveness of antibodies produced by memory B cells, the long-lasting immune cells that recall past infections.
“We discovered that individuals with a genetic deficiency in PD-1 or PD-L1 have a less diverse range of antibodies and fewer memory B cells, which hampers their ability to produce high-quality antibodies against common infections like viruses and bacteria,” says Dr. Masato Ogishi, the study’s first author from Rockefeller University.
Professor Tangye adds, “This reduced generation and effectiveness of memory B cells could clarify the higher infection rates seen in cancer patients receiving checkpoint inhibitors.”
Co-author Dr. Kenji Chamoto from Kyoto University states, “The effect of inhibiting PD-1 has a ‘yin and yang’ quality: it boosts anti-tumor immunity while simultaneously hindering B-cell immunity. This duality appears to arise from a fundamental mechanism of immune balance.”
New guidance for healthcare providers
The researchers emphasize that their findings underscore the importance of monitoring B cell functions in patients receiving checkpoint inhibitors and suggest preventative strategies for those who are at an elevated risk of infections.
Co-senior author Dr. Stéphanie Boisson-Dupuis from Rockefeller University notes, “While PD-1 inhibitors have significantly advanced cancer treatment, our findings highlight the need for clinicians to recognize the possible trade-offs between enhanced anti-cancer immunity and decreased antibody-mediated defenses.”
“One viable preventative measure is immunoglobulin replacement therapy (IgRT), an established treatment that replenishes missing antibodies in immunodeficient patients and could be considered for cancer patients more susceptible to infections,” she adds.
Transforming rare cases into broader benefits
“Researching rare genetic disorders like PD-1 or PD-L1 deficiencies allows us to gain valuable insights into the normal functioning of the human immune system and how intervening in it can have significant impacts. Thanks to these cases, we’ve identified pathways to fine-tune cancer immunotherapies for maximum benefit and minimal harm,” says Professor Tangye.
Looking forward, the researchers aim to find ways to enhance checkpoint inhibitor treatments to maintain their strong anti-cancer effects while safeguarding the immune system’s ability to fend off infections.
“This study illustrates the potential for cancer, genomics, and immunology research to benefit each other, leading to discoveries that could positively impact the wider community,” concludes Professor Tangye.
