An international team led in part by the Garvan Institute of Medical Research has found a possible explanation for why certain cancer patients who undergo checkpoint inhibitor immunotherapy face heightened risks of common infections.
Detailed in the publication Immunity, these findings enhance our comprehension of immune reactions and suggest methods for reducing this frequent side effect linked to cancer treatments.
“Checkpoint inhibitor therapies have transformed cancer care by enabling T cells to target tumors and cancer cells more efficiently. However, this advancement comes with challenges. Roughly 20% of cancer patients on these treatments develop higher infection rates, a previously little-understood issue,” states Professor Stuart Tangye, a co-lead author and Head of the Immunology and Immunodeficiency Lab at Garvan.
“Our research shows that while these inhibitors strengthen anti-cancer defenses, they might also weaken B cells, the immune system components responsible for producing antibodies against infections. Recognizing this is vital in addressing and decreasing immunity-related side effects of such treatments.”
The investigation zeroed in on the molecule PD-1, acting as an immune system ‘handbrake’ that prevents T cells from overactivation. Checkpoint inhibitors work by releasing this ‘handbrake,’ boosting the immune system’s cancer-fighting capabilities.
In collaboration with Rockefeller University in the USA and Kyoto University Graduate School of Medicine in Japan, the study analyzed immune cells from patients with genetic deficiencies in PD-1 or its partner PD-L1 and animal models lacking PD-1 signaling. Results showed that deficient or absent PD-1 activity can greatly undermine the diversity and effectiveness of antibodies from memory B cells — crucial long-lived cells remembering past infections.
“We observed individuals born without PD-1 or PD-L1 have less antibody diversity and fewer memory B cells, complicating their ability to generate strong antibodies against common pathogens,” explains Dr. Masato Ogishi, the study’s lead author from Rockefeller University.
Professor Tangye explains, “The reduction in memory B cell quality and production might clarify the increased infections seen in cancer patients undergoing checkpoint inhibitor treatment.”
Dr. Kenji Chamoto from Kyoto University remarks, “PD-1 blocking has a dual nature: it energizes tumor-targeting immunity but simultaneously hinders B-cell immunity, attributed to an intrinsic mechanism ensuring immune balance.”
The findings stress the importance of evaluating B cell function in patients on checkpoint inhibitors and suggest preemptive measures for those at higher infection risk.
Dr. Stéphanie Boisson-Dupuis of Rockefeller University, a co-senior author, states, “While PD-1 inhibitors enhance cancer management, they imply a trade-off between improved tumor-attack immunity and reduced antibody-based immunity.”
“Immunoglobulin replacement therapy (IgRT) is a potential intervention to preemptively protect cancer patients prone to more infections,” she advises.
Examining rare genetic conditions like PD-1 or PD-L1 deficiencies offers deep insights into the typical operation of the human immune system and the impacts of our manipulations. Professor Tangye adds, “These patients provide paths for optimizing cancer immunotherapies for maximum gain with minimum risk.”
Future research will focus on refining checkpoint inhibitor therapy to maintain its potent cancer-fighting benefits while preserving the immune system’s infection-fighting capabilities.
Professor Tangye concludes, “This work exemplifies how research collaboration across cancer, genomics, and immunology can generate innovations beneficial to the wider community.”
Professor Stuart Tangye holds a concurrent position as a Conjoint Professor at St Vincent’s Clinical School, Faculty of Medicine and Health, UNSW Sydney.