In a paradigm breaking study, Dr. Pavan Reddy, director of the Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine (BCM) and his team, in collaboration with Drs. Arul Chinnaiyan, S P Hicks Endowed Professor of Pathology, and Marcin Cieslik, assistant professor of pathology, both from University of Michigan Rogel Cancer Center, discovered a novel way the immune system, specifically T-cells, attack their target cells, reshaping long-held assumptions in immunology and demonstrating direct implications for the field of cancer immunology and bone marrow transplantation. The study appeared in Nature Immunology.
The immune system relies on molecules called major histocompatibility complexes (MHC) to detect external ‘threats’ to the body, including from cancerous or foreign (allogeneic) cells. Historically, MCH class I molecules were believed to present signals only to CD8+ T cells (‘killer’ T cells), while MHC II activated CD4+ T cells (‘helper’ T cells). This division of MHC class roles guided decades of immunology and cancer research.
In an example of collaborative work, Reddy’s graduate students Emma Lauder and Meng-Chih Wu from BCM and Chinnaiyan and Cieslik’s student Mahnoor Gondal, from University of Michigan worked with colleagues on various components of the work that spanned several years. The work challenges this foundational MHC class-restricted dichotomy and reveals a previously unrecognized role for class I pathway in CD4+ T cell mediated immune defense.
Utilizing advanced transcriptomic and functional studies in experimental mice models and humans, Reddy and colleagues demonstrate that when cancer cells lose MHC I expression – a common strategy to evade CD8+ T cell attack – they become more vulnerable to attack from CD4+ T cells. The authors found that, without MHC I expression, cancer cells are more sensitive to ferroptosis triggered by CD4+ T cells. Ferroptosis is a type of cell death driven by iron and oxidative stress.
The induction of ferroptosis occurred not only in cancer, but also in models of graft-versus-host disease, a significant complication of bone marrow transplant. Chinnaiyan’s team demonstrated that these observations correlated with clinical outcomes by analyzing large transcriptomic and clinical datasets from patients who received checkpoint blocker therapy for solid tumor cancers.
This work shows that reducing expression of MHC I enhances CD4+ T cell-driven killing of target cells, whether allogeneic or cancerous. New strategies to harness these so-called ‘helpers’ could make immunotherapies more potent, especially against tumors that evade CD8+ T cell responses, while also suggesting a role for MHC class I in regulating tissue sensitivity to CD4+ T cell-mediated attack.
“Our work, if further validated, will have implications for T cell-mediated immune responses beyond cancer and transplant immunology,” Reddy said. “This may allow for the development of novel strategies that target MHC class I and CD4+ T cells to leverage the beneficial side of immunity or mitigate unwanted immune responses.”
Emma Lauder, Mahnoor Gondal, Meng-Chih Wu, Akira Yamamoto, Laure Maneix, Dongchang Zhao and Yaping Sun also contributed to this work. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, University of Michigan and Howard Hughes Medical Institute.
This work was supported by NIH grants (P01CA039542, P01HL149633, R01HL152605, R01CA217156, R01AI165563, CA125123, OD036336, and OD038251) and by Cancer Prevention and Research Institute of Texas grants (RR220033 and RP240432).
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