Rare Genetic Disorder Helps Explain Link Between Cancer Immunotherapy and Increased Infections

A multinational collaboration co-led by the Garvan Institute of Medical Research,  in collaboration with Rockefeller University, and Kyoto University Graduate School of Medicine, has uncovered a potential explanation for why some cancer patients receiving checkpoint inhibitor immunotherapy experience increased susceptibility to common infections.

The findings offer up new insights into immune responses and reveal a potential approach to preventing the common cancer therapy side effect.

“Immune checkpoint inhibitor therapies have revolutionized cancer treatment by allowing T cells to attack tumors and cancer cells more effectively,” said Stuart Tangye, PhD, head of the Immunology and Immunodeficiency Lab at Garvan. “But this hasn’t been without side effects—one of which is that approximately 20% of cancer patients undergoing checkpoint inhibitor treatment experience an increased incidence of infections, a phenomenon that was previously poorly understood.”

Tangye is co-senior author of the team’s published paper in Immunity, titled “Impaired development of memory B cells and antibody responses in humans and mice deficient in PD-1 signaling.”

For their study, the researchers focused on the molecule PD-1, which acts as a “handbrake” on the immune system, preventing overactivation of T cells. Checkpoint inhibitor therapies work by releasing this molecular handbrake to enhance the immune system’s ability to fight cancer. “Neutralizing antibodies (nAbs) against PD-1 and PD-L1, which are widely used in cancer immunotherapy, unleash T cell-mediated immunity to self- and tumor-derived antigens (Ags),” the investigators stated.

However, as the team also pointed out, “… evidence suggests that an adverse consequence of PD-1/PD-L1-mediated cancer immunotherapy in humans is an increased frequency of bacterial infections, irrespective of treatment with other immunosuppressive reagents.”

The researchers examined the immune cells of 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. They found that impaired or absent PD-1 activity can significantly reduce the diversity and quality of antibodies produced by memory B cells—the long-lived immune cells that ‘remember’ past infections.

“Our findings indicate that while checkpoint inhibitors boost anti-cancer immunity, they can also handicap B cells, which are the cells of the immune system that produce antibodies to protect against common infections,” Tangye said. “This understanding is a critical first step in understanding and reducing the side effects of this cancer treatment on immunity.”

“We found that people 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,” added first author Masato Ogishi, PhD, currently a postdoc at Stanford University.

Professor Tangye further commented, “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.”

The authors noted that, importantly, PD-1- and PDL1-deficient patients had not yet manifested any severe bacterial infections that typically occur in patients with antibody deficiency, “… suggesting that the observed defects in humoral immunity are probably insufficient to cause clinically overt phenotypes during childhood.” They also pointed out that most cancer patients on PD-1 or PDL1 blockade immunotherapy are already immunocompromised due to type of malignancy, comorbidity, and older age. “Thus, subtle perturbations of humoral immunity due to PD-1 or PD-L1 blockade can potentially trigger devastating bacterial infections,” they wrote.

Co-author Kenji Chamoto, PhD, professor at Kyoto University, noted, “PD-1 inhibition has a ‘yin and yang’ nature: it activates anti-tumor immunity but at the same time impedes B-cell immunity. And this duality seems to stem from a conserved mechanism of immune homeostasis.”

The researchers say the findings highlight the need for clinicians to monitor B cell function in patients receiving checkpoint inhibitors and point to preventative interventions for 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 anti-tumor immunity and impaired antibody-mediated immunity,” stated Stéphanie Boisson-Dupuis, PhD, researcher from Rockefeller University. “One potential preventative solution is immunoglobulin replacement therapy (IgRT), an existing treatment used to replace missing antibodies in patients with immunodeficiencies, which could be considered as a preventative measure for cancer patients at higher risk of infections.”

Studying cases of rare genetic conditions such as PD-1 or PD-L1 deficiency enabled the team to gain what Tangye calls 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.”

In their paper the investigators suggested that their findings “… should prompt further investigations into the frequency and severity of bacterial and other infections and the potential clinical benefits of prophylactic vaccination (e.g., S. pneumoniae and H. influenzae) and low-dose intravenous Ig in cancer patients on PD-1 or PD-L1 blockade immunotherapy.”

Looking ahead, the researchers will explore ways to refine checkpoint inhibitor treatments to maintain their powerful anti-cancer effects while preserving the immune system’s ability to fight infections. “This research highlights the potential for cancer, genomics and immunology research to inform one another, enabling discoveries that can benefit the broader population,” Tangye said.

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