New insights into the influence of checkpoint inhibitors on the immune system could improve most cancers therapy methods.
A multinational workforce, co-led by the Garvan Institute of Medical Research, has recognized a potential cause why some most cancers sufferers handled with checkpoint inhibitor immunotherapy could turn out to be extra susceptible to frequent infections.
The findings, revealed within the journal Immunity, present new insights into immune responses and reveal a possible method to stopping the frequent most cancers remedy facet impact.
“Immune checkpoint inhibitor therapies have revolutionized cancer treatment by allowing T cells to attack tumors and cancer cells more effectively. 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,” says Professor Stuart Tangye, co-senior writer of the research and Head of the Immunology and Immunodeficiency Lab at Garvan.
“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. This understanding is a critical first step in understanding and reducing the side effects of this cancer treatment on immunity.”
Insights to enhance immunotherapy
The researchers targeted on the molecule PD-1, which acts as a ‘handbrake’ on the immune system, stopping the overactivation of T cells. Checkpoint inhibitor therapies work by releasing this molecular ‘handbrake’ to reinforce the immune system’s capability to struggle most cancers.
The research, which was carried out in collaboration with Rockefeller University within the USA and Kyoto University Graduate School of Medicine in Japan, examined the immune cells of sufferers with uncommon circumstances of genetic deficiency of PD-1, or its binding companion PD-L1, in addition to animal fashions missing PD-1 signaling. The researchers discovered that impaired or absent PD-1 exercise can considerably scale back the variety and high quality of antibodies produced by reminiscence B cells – the long-lived immune cells that ‘remember’ previous infections.
“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,” says Dr Masato Ogishi, first writer of the research, from Rockefeller University.
Professor Tangye provides: “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.”
Co-author Dr Kenji Chamoto, from Kyoto University, says, “PD-1 inhibition has a ‘yin and yang’ nature: it activates anti-tumour immunity but at the same time impedes B-cell immunity. And this duality seems to stem from a conserved mechanism of immune homeostasis.”
New suggestion for clinicians
The researchers say the findings spotlight the necessity for clinicians to watch B cell operate in sufferers receiving checkpoint inhibitors and level to preventative interventions for these at larger threat of infections.
Co-senior writer Dr Stéphanie Boisson-Dupuis, from Rockefeller University, says, “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-tumour immunity and impaired antibody-mediated immunity.”
“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,” she says.
From uncommon circumstances to insights to profit all
“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,” says Professor Tangye.
Looking forward, the researchers will discover methods to refine checkpoint inhibitor therapies to keep up their highly effective anti-cancer results whereas preserving the immune system’s capability to struggle infections.
“This research highlights the potential for cancer, genomics, and immunology research to inform one another, enabling discoveries that can benefit the broader population,” says Professor Tangye.
Reference: “Impaired development of memory B cells and antibody responses in humans and mice deficient in PD-1 signaling” by Masato Ogishi, Koji Kitaoka, Kim L. Good-Jacobson, Darawan Rinchai, Baihao Zhang, Jun Wang, Vincent Gies, Geetha Rao, Tina Nguyen, Danielle T. Avery, Taushif Khan, Megan E. Smithmyer, Joseph Mackie, Rui Yang, Andrés Augusto Arias, Takaki Asano, Khoren Ponsin, Matthieu Chaldebas, Peng Zhang, Jessica N. Peel, Jonathan Bohlen, Romain Lévy, Simon J. Pelham, Wei-Te Lei, Ji Eun Han, Iris Fagniez, Maya Chrabieh, Candice Laine, David Langlais, Conor Gruber, Fatima Al Ali, Mahbuba Rahman, Caner Aytekin, Basilin Benson, Matthew J. Dufort, Clara Domingo-Vila, Kunihiko Moriya, Mark Shlomchik, Gulbu Uzel, Paul E. Gray, Daniel Suan, Kahn Preece, Ignatius Chua, Satoshi Okada, Shunsuke Chikuma, Hiroshi Kiyonari, Timothy I. Tree, Dusan Bogunovic, Philippe Gros, Nico Marr, Cate Speake, Richard A. Oram, Vivien Béziat, Jacinta Bustamante, Laurent Abel, Bertrand Boisson, Anne-Sophie Korganow, Cindy S. Ma, Matthew B. Johnson, Kenji Chamoto, Stéphanie Boisson-Dupuis, Tasuku Honjo, Jean-Laurent Casanova and Stuart G. Tangye, 26 November 2024, Immunity.
DOI: 10.1016/j.immuni.2024.10.014
