Researchers may have uncovered the factors contributing to an increased susceptibility to common infections among patients with cancer receiving checkpoint inhibitors, according to a recent study published by Ogishi et al in Immunity. The findings may provide new insights into immune responses and reveal a potential approach to prevent adverse effects following cancer therapy.
Background
The molecule PD-1 acts like a brake on the immune system, preventing overactivation of T cells. Checkpoint inhibitor therapies work by releasing this molecular brake to enhance the immune system’s ability to fight cancer. Memory B cells are the long-lived immune cells that “remember” past infections.
“Immune checkpoint inhibitor therapies have revolutionized cancer treatment by allowing T cells to attack tumors and cancer cells more effectively. [However], this hasn’t been without side effects—one of which is that approximately 20% of [patients with] cancer undergoing checkpoint inhibitor treatment experience an increased incidence of infections, a phenomenon that was previously poorly understood,” explained co–senior study author Stuart Tangye, PhD, Conjoint Professor at St. Vincent's Clinical School in the Faculty of Medicine and Health at the University of New South Wales Sydney and Head of the Immunology and Immunodeficiency Laboratory at the Garvan Institute of Medical Research.
“Our findings indicate that while checkpoint inhibitors boost anticancer immunity, they can also handicap B cells, which are the cells of the immune system that produce antibodies to protect against common infections. This understanding is a critical first step in understanding and reducing the side effects of this cancer treatment on immunity,” he noted.
Study Methods and Results
In the recent study, the researchers examined immune cells in patients with rare cases of genetic deficiency of PD-1 or its binding partner PD-L1 as well as animal models lacking PD-1 signaling.
The researchers found that impaired or absent PD-1 activity may reduce the diversity and quality of antibodies produced by memory B cells.
“We found that [patients] born with a deficiency in PD-1 or PD-L1 have reduced diversity in their antibodies and fewer memory B cells, which made it harder to generate high-quality antibodies against common pathogens such as viruses and bacteria,” emphasized lead study author Masato Ogishi, MD, PhD, of Rockefeller University.
“This dampening of the generation and quality of memory B cells could explain the increased rates of infection reported in patients with cancer receiving checkpoint inhibitor therapy,” Dr. Tangye indicated.
“PD-1 inhibition has a ‘yin and yang’ nature: it activates antitumor immunity but at the same time impedes B-cell immunity. [T]his duality seems to stem from a conserved mechanism of immune homeostasis,” detailed co–study author Kenji Chamoto, PhD, of Kyoto University.
Conclusions
The findings highlighted the need for clinicians to monitor B-cell function in patients receiving checkpoint inhibitors and pointed to preventative interventions among those at higher risk of infections.
“Although PD-1 inhibitors have greatly improved cancer care, our findings indicate that clinicians need to be aware of the potential trade-off between enhanced antitumour immunity and impaired antibody-mediated immunity,” suggested co–senior study author Stéphanie Boisson-Dupuis, PhD, of Rockefeller University. “One potential preventive solution is immunoglobulin replacement therapy, an existing treatment used to replace missing antibodies in patients with immunodeficiencies, which could be considered as a preventative measure for patients [with cancer] at higher risk of infections,” she continued.
The researchers plan to explore strategies to refine checkpoint inhibitor treatments to maintain their powerful anticancer effects while preserving the immune system’s ability to fight infections.
“Studying cases of rare genetic conditions such as PD-1 or PD-L1 deficiency enables us to gain profound insights into how the human immune system normally works, and how our own manipulation of it can affect it. Thanks to these patients, we’ve found an avenue for fine-tuning cancer immunotherapies to maximize benefit while minimizing harm,” Dr. Tangye underscored. “This research highlights the potential for cancer, genomics, and immunology research to inform one another, enabling discoveries that can benefit the broader population,” he concluded.
Disclosure: For full disclosures of the study authors, visit cell.com.
