Article
Multidisciplinary Sciences
Yuankun Zhang, Qingxiao Song, Kaniel Cassady, Michael Lee, Haidong Tang, Moqian Zheng, Bixin Wang, Dustin E. Schones, Yang-Xin Fu, Arthur D. Riggs, Paul J. Martin, Ru Feng, Defu Zeng
Summary: Previous assumptions about PD-L1/CD80 interactions being trans have been challenged by recent reports, which suggest that these interactions are actually cis. Blocking PD-L1/CD80 interactions on antigen-presenting cells has been found to reduce antitumor immunity, while blocking both cis and trans interactions or just the trans interactions can enhance antitumor immunity by increasing IFN-γ-producing CD8+ T cells and IFN-γ-dependent NOS2-expressing tumor-associated macrophages. Overall, blocking PD-L1/CD80 interactions in vivo has a net positive effect on CD8+ T cell-mediated antitumor immunity.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2023)
Article
Biochemistry & Molecular Biology
Alan Kennedy, Maximillian A. Robinson, Claudia Hinze, Erin Waters, Cayman Williams, Neil Halliday, Simon Dovedi, David M. Sansom
Summary: CTLA-4 and PD-1 are immune checkpoint receptors targeted in cancer treatment. A recent discovery shows that the interaction between their respective ligands, CD80 and PD-L1, can block PD-L1/PD-1 binding and inhibit PD-L1 functions. The internalization of CD80 results in the recovery of PD-L1 availability, while CD80/PD-L1 complexes remain on the plasma membrane. CTLA-4 modulates PD-L1:PD-1 interactions by controlling CD80.
Article
Oncology
Jin-Yuan Liu, Zi-Li Yu, Qiu-Yun Fu, Lin-Zhou Zhang, Jin-Bang Li, Min Wu, Bing Liu, Gang Chen
Summary: This study found that PD-L1-positive sEVs in head and neck squamous cell carcinoma patients have different cellular origins, including tumor cells, T cells, B cells, dendritic cells, and monocyte/macrophages. However, PD-L1-positive sEVs derived from immune cells do not have immunosuppressive effects due to the co-expression of CD80. The co-expression of CD80 restricts the immunosuppressive effect of sEV PD-L1.
BRITISH JOURNAL OF CANCER
(2023)
Review
Microbiology
Takayuki Murata
Summary: The immune system's activation and regulated downregulation are crucial for preventing immune disorders. The PD-1/PD-L1 pathway benefits the host but can also be exploited by pathogens to evade immunity. Herpesviruses like HSV, CMV, and EBV have complex relationships with this pathway and understanding them is essential for developing effective preventative and therapeutic methods.
Article
Multidisciplinary Sciences
Murat Tekguc, James Badger Wing, Motonao Osaki, Jia Long, Shimon Sakaguchi
Summary: Regulatory T cells reduce the expression of CD80/CD86 on antigen-presenting cells through CTLA-4-dependent trogocytosis, inhibiting T cell immune responses. This mechanism can have dual suppressive effects, limiting CD80/CD86 costimulation to naive T cells and increasing free PD-L1 available for the inhibition of PD-1-expressing effector T cells.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Review
Oncology
Yasser Tabana, Isobel S. Okoye, Arno Siraki, Shokrollah Elahi, Khaled H. Barakat
Summary: Breast cancer poses a significant global problem, with recent focus on immunotherapy as a new approach to treatment. However, there are limitations to immune checkpoint inhibitors in treating breast cancer, leading researchers to explore novel immunological targets to modulate the tumor immune microenvironment.
FRONTIERS IN ONCOLOGY
(2021)
Article
Engineering, Biomedical
Eun-Koung An, Wei Zhang, Hae-Bin Park, So-Jung Kim, Hee-Yun Eom, Juyoung Hwang, Minseok Kwak, Ji Yeon Lee, Peter Chang-Whan Lee, Jun-O Jin
Summary: In this study, recombinant murine PD-L1 (rmPD-L1) was used to control T cell immunity and treat multi-organ inflammation. Hybrid nanoparticles (HNPs) were developed by incorporating the anti-inflammatory drug methotrexate and decorating the surface with rmPD-L1, resulting in immunosuppressive HNPs (IsHNPs). IsHNP treatment effectively targeted PD-1-expressing CD4 and CD8 T cells, promoted the production of regulatory T cells, and inhibited the activation of CD4 and CD8 T cells. This study demonstrates the therapeutic potential of IsHNPs for multi-organ inflammation and other inflammatory diseases.
Article
Biochemistry & Molecular Biology
Lu Cao, Kim R. Bridle, Ritu Shrestha, Prashanth Prithviraj, Darrell H. G. Crawford, Aparna Jayachandran
Summary: Gallbladder cancer is a highly aggressive form of biliary tract cancer, and current clinical trials are examining the effectiveness of immune checkpoint inhibitors as monotherapy. However, only select patients respond to these treatments. This study investigates the molecular mechanisms that contribute to resistance to immune checkpoint blockade and identifies epithelial-to-mesenchymal transition and cancer stem cells as key factors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Microbiology
Harry H. Matundan, Ujjaldeep Jaggi, Jack Yu, Omid Akbari, Homayon Ghiasi
Summary: This study found that the interactions between CD28, CTLA4, and PD-L1 with CD80 can affect HSV-1 reactivation, leading to lower interferon signaling and reduced virus reactivation levels. Blocking these interactions could be a potential therapeutic target for HSV-1-induced reactivation and associated eye diseases.
Article
Oncology
Meng Wei, Yunhai Mo, Jialong Liu, Jingtong Zhai, Huilong Li, Yixin Xu, Yumeng Peng, Zhihong Tang, Tao Wei, Xiaopan Yang, Linfei Huang, Xiao Shao, Jingfei Li, Li Zhou, Hui Zhong, Congwen Wei, Qiaosheng Xie, Min Min, Feixiang Wu
Summary: This study reveals a novel mechanism in regulating PD-L1 expression involving the interaction between PD-L1 and RNF125. Overexpression of RNF125 leads to decreased PD-L1 levels and delayed tumor growth, while patients with higher RNF125 expression have better clinical outcomes. These findings may provide a new strategy to enhance the efficacy of immunotherapy.
FRONTIERS IN ONCOLOGY
(2022)
Article
Biochemistry & Molecular Biology
Tara Kang-Pettinger, Kayleigh Walker, Richard Brown, Richard Cowan, Helena Wright, Roberta Baravalle, Lorna C. Waters, Frederick W. Muskett, Matthew W. Bowler, Kovilen Sawmynaden, Peter J. Coombs, Mark D. Carr, Gareth Hall
Summary: Programmed death-ligand 1 (PD-L1) interacts with programmed cell death protein 1 (PD-1), leading to T-cell suppression. Cancer cells overexpress PD-L1 to evade the immune system. Inhibition of the PD-1/PD-L1 pathway with monoclonal antibodies has been effective in cancer treatment, but single domain antibodies (VHH) may offer additional benefits. We identified and characterized 16 novel VHHs specific to PD-L1, which showed high affinities and complete inhibition of PD-1 binding.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2023)
Article
Multidisciplinary Sciences
Chih-Hao Lu, Wei-Min Chung, Chun-Hao Tsai, Ju-Chien Cheng, Kai-Cheng Hsu, Huey-En Tzeng
Summary: The study identified a small molecule inhibitor, CH-4, that effectively blocks the interaction between PD-1 and PD-L1, offering a potential alternative target for immune checkpoint therapy.
SCIENTIFIC REPORTS
(2022)
Article
Oncology
Manuel Weber, Rainer Lutz, Manuel Olmos, Jacek Glajzer, Christoph Baran, Christopher-Philipp Nobis, Tobias Moest, Markus Eckstein, Marco Kesting, Jutta Ries
Summary: This study aimed to identify potential targets for therapeutic applications in oral squamous cell carcinoma (OSCC) by analyzing the expression levels of various immune modulators. The results showed increased expression of inhibitory receptors and ligands, as well as downregulation of activators in OSCC, suggesting a potential mechanism for immune escape. The study contributes to the understanding of immune evasion in OSCC and provides potential targets for immunotherapy.
Article
Immunology
Qi Zhang, Jing Pan, Donghai Xiong, Junjun Zheng, Kristi N. McPherson, Sangbeom Lee, Mofei Huang, Yitian Xu, Shu-hsia Chen, Yian Wang, Lea Hildebrandt Ruiz, Ming You
Summary: Delivery of aerosolized microRNAs targeting PD-L1 can effectively prevent the development and progression of lung cancer. In this study, aerosolized miR-138-5p and miR-200c miRNA mimics were found to inhibit B(a)P-induced lung adenomas and NTCU-induced lung squamous cell carcinomas with no detectable side effects. These miRNAs were also shown to inhibit PD-L1 expression and promote the immune response against cancer cells by increasing CD4+ and CD8+ T cells while reducing PD-1 expression and T-regulatory cells.
FRONTIERS IN IMMUNOLOGY
(2023)
Article
Oncology
Ashkan Shahbandi, Fang-Yen Chiu, Nathan A. A. Ungerleider, Raegan Kvadas, Zeinab Mheidly, Meijuan J. S. Sun, Di Tian, Daniel A. A. Waizman, Ashlyn Y. Y. Anderson, Heather L. L. Machado, Zachary F. F. Pursell, Sonia G. G. Rao, James G. G. Jackson
Summary: Breast cancer cells surviving chemotherapy activate complex immune modulation programs, with residual disease characterized by interferon response genes and p53 signaling.
Article
Oncology
Kathleen M. Mahoney, Petra Ross-Macdonald, Long Yuan, Linan Song, Eliseo Veras, Megan Wind-Rotolo, David F. McDermott, F. Stephen Hodi, Toni K. Choueiri, Gordon J. Freeman
Summary: This study investigated the levels of soluble PD-L1 (sPD-L1) before and during nivolumab treatment in metastatic clear cell renal cell carcinoma (RCC) and melanoma patients. The results showed that sPD-L1 levels were associated with worse prognosis and clinical factors. Additionally, changes in sPD-L1 levels during treatment were linked to treatment outcomes.
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2022)
Article
Multidisciplinary Sciences
Wenjun Xiong, Xueliang Gao, Tiantian Zhang, Baishan Jiang, Ming-Ming Hu, Xia Bu, Yang Gao, Lin-Zhou Zhang, Bo-Lin Xiao, Chuan He, Yishuang Sun, Haiou Li, Jie Shi, Xiangling Xiao, Bolin Xiang, Conghua Xie, Gang Chen, Haojian Zhang, Wenyi Wei, Gordon J. Freeman, Hong-Bing Shu, Haizhen Wang, Jinfang Zhang
Summary: The study reveals how USP8 affects the efficacy of PD-1/PD-L1 immunotherapy by regulating PD-L1 protein abundance and activating the NF-kappa B signaling pathway, which in turn inhibits tumor growth by reshaping the tumor microenvironment and triggering immune responses.
NATURE COMMUNICATIONS
(2022)
Article
Oncology
Carlos R. Gil Del Alcazar, Anne Trinh, Alec Kovic, Ernesto Rojas Jimenez, Nicholas W. Harper, Michael U. J. Oliphant, Shanshan Xie, Ethan D. Krop, Bethlehem Lulseged, Katherine C. Murphy, Tanya E. Keenan, Eliezer M. Van Allen, Sara M. Tolaney, Gordon J. Freeman, Deborah A. Dillon, Senthil K. Muthuswamy, Kornelia Polyak
Summary: This study demonstrates the importance of a new breast cancer model for preclinical studies in cancer immunotherapy. The model accurately reproduces the molecular subtypes and immune characteristics of human breast cancer, and identifies markers of treatment response and resistance through gene expression profiling and spatial mapping. This provides a new research direction for immunotherapy in breast cancer.
CANCER IMMUNOLOGY RESEARCH
(2022)
Article
Immunology
Stinne R. Greisen, Tue W. Kragstrup, Jesper Skovhus Thomsen, Kim Horslev-Pedersen, Merete Lund Hetland, Kristian Stengaard-Pedersen, Mikkel Ostergaard, Lykke Ornbjerg, Peter Junker, Arlene H. Sharpe, Gordon J. Freeman, Malene Hvid, Soren K. Moestrup, Ellen Margrethe Hauge, Bent Deleuran
Summary: The PD-1 pathway is closely associated with bone homeostasis, and lacking members of this pathway causes a deteriorated bone structure. In early rheumatoid arthritis patients, soluble PD-1 may serve as a biomarker, reflecting residual but clinically silent disease activity and radiographic progression.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Oncology
Yufei Wang, Alicia Buck, Marion Grimaud, Aedin C. Culhane, Sreekumar Kodangattil, Cecile Razimbaud, Dennis M. Bonal, Quang-De Nguyen, Zhu Zhu, Kevin Wei, Madison L. O'Donnell, Ying Huang, Sabina Signoretti, Toni K. Choueiri, Gordon J. Freeman, Quan Zhu, Wayne A. Marasco
Summary: Improving CAR-T cell therapy for solid tumors requires a better understanding of CAR design and cellular composition. A study found that CAR-T cells with a CD4/CD8 ratio of BB zeta exhibited superior efficacy in clearing clear-cell renal cell carcinoma (ccRCC) in a mouse model, demonstrating long-term tumor-free outcome.
MOLECULAR THERAPY-ONCOLYTICS
(2022)
Article
Cell Biology
Ilaria Elia, Jared H. Rowe, Sheila Johnson, Shakchhi Joshi, Giulia Notarangelo, Kiran Kurmi, Sarah Weiss, Gordon J. Freeman, Arlene H. Sharpe, Marcia C. Haigis
Summary: This study reveals the mechanism by which tumor-derived lactate in the tumor microenvironment inhibits the cytotoxicity of CD8(+) T cells, highlighting the role of metabolic pathways in regulating T cell cytotoxicity.
Article
Oncology
Thomas Denize, Yue Hou, Jean-Christophe Pignon, Emily Walton, Destiny J. West, Gordon J. Freeman, David A. Braun, Catherine J. Wu, Saurabh Gupta, Robert J. Motzer, Michael B. Atkins, David McDermott, Toni K. Choueiri, Sachet A. Shukla, Sabina Signoretti
Summary: The study explores the molecular correlates of TC PD-L1 expression in ccRCC and its predictive role in anti-PD-1 monotherapy. The results show that TC PD-L1 expression is associated with overexpression of immune-and cell proliferation-related pathways, upregulation of T-cell activation signatures, and increased tumor-infiltrating immune cells. Additionally, a specific molecular RCC subtype enriched in TC PD-L1 positive tumors is found to have longer progression-free survival and higher objective response rate.
CLINICAL CANCER RESEARCH
(2022)
Article
Medicine, Research & Experimental
Sarah C. Cowles, Allison Sheen, Luciano Santollani, Emi A. Lutz, Brianna M. Lax, Joseph R. Palmeri, Gordon J. Freeman, K. Dane Wittrup
Summary: Monoclonal antibodies targeting PD-1 show varied efficacy depending on their affinity, and a threshold affinity is required for maximum efficacy in the treatment of MC38 adenocarcinoma.
Article
Multidisciplinary Sciences
Vijayakumar Velu, Kehmia Titanji, Hasan Ahmed, Ravi Dyavar Shetty, Lakshmi S. Chennareddi, Gordon J. Freeman, Rafi Ahmed, Rama Rao Amara
Summary: The study demonstrated that PD-1 blockade following ART interruption significantly enhances the function of anti-viral CD8 T cells and improves viral control. It suggests the potential synergistic effects of PD-1 blockade with other immunotherapies inducing functional CD8 T-cell responses.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2022)
Correction
Immunology
Christopher S. Garris, Sean P. Arlauckas, Rainer H. Kohler, Marcel P. Trefny, Seth Garren, Cecile Piot, Camilla Engblom, Christina Pfirschke, Marie Siwicki, Jeremy Gungabeesoon, Gordon J. Freeman, Sarah E. Warren, SuFey Ong, Erica Browning, Christopher G. Twitty, Robert H. Pierce, Mai H. Le, Alain P. Algazi, Adil I. Daud, Sara I. Pai, Alfred Zippelius, Ralph Weissleder, Mikael J. Pittet
Article
Multidisciplinary Sciences
Masao Hashimoto, Koichi Araki, Maria A. Cardenas, Peng Li, Rohit R. Jadhav, Haydn T. Kissick, William H. Hudson, Donald J. McGuire, Rebecca C. Obeng, Andreas Wieland, Judong Lee, Daniel T. McManus, James L. Ross, Se Jin Im, Junghwa Lee, Jian-Xin Lin, Bin Hu, Erin E. West, Christopher D. Scharer, Gordon J. Freeman, Arlene H. Sharpe, Suresh S. Ramalingam, Alex Pellerin, Volker Teichgraber, William J. Greenleaf, Christian Klein, Jorg J. Goronzy, Pablo Umana, Warren J. Leonard, Kendall A. Smith, Rafi Ahmed
Summary: The study showed that combination therapy with PD-1 blockade and IL-2 during chronic lymphocytic choriomeningitis virus infection significantly alters the differentiation program of CD8(+) T cells, resulting in the generation of highly functional effector CD8(+) T cells that mediate viral control, thus providing a new perspective for cancer treatment.
Article
Oncology
Liya Ding, Qiwei Wang, Antons Martincuks, Michael J. Kearns, Tao Jiang, Ziying Lin, Xin Cheng, Changli Qian, Shaozhen Xie, Hye-Jung Kim, Inga-Maria Launonen, Anniina Faerkkilae, Thomas M. Roberts, Gordon J. Freeman, Joyce F. Liu, Panagiotis A. Konstantinopoulos, Ursula Matulonis, Hua Yu, Jean J. Zhao
Summary: This study reveals an adaptive immunosuppression mechanism that leads to resistance to PARP inhibition in BRCA1-mutant ovarian tumors. This resistance is mediated by an increased population of protumor tumor-associated macrophages (TAMs) and activation of the STAT3 signaling pathway. The use of STING agonists can reshape the immunosuppressive tumor microenvironment and overcome PARPi resistance in ovarian cancer.
JOURNAL FOR IMMUNOTHERAPY OF CANCER
(2023)
Article
Multidisciplinary Sciences
Heng-Jia Liu, Heng Du, Damir Khabibullin, Mahsa Zarei, Kevin Wei, Gordon J. Freeman, David J. Kwiatkowski, Elizabeth P. Henske
Summary: This study reveals that B7-H3 expression is correlated with immunosuppressive phenotypes and worse clinical outcomes in human tumors with high mTORC1 activity. The authors show that mTORC1 upregulates B7-H3 expression by phosphorylating the transcription factor YY2. Inhibiting B7-H3 enhances T-cell activity and induces tumor cell expression of MHC-II, suppressing tumor growth with mTORC1 hyperactivity.
NATURE COMMUNICATIONS
(2023)
Article
Multidisciplinary Sciences
Jing Liu, Xia Bu, Chen Chu, Xiaoming Dai, John M. Asara, Piotr Sicinski, Gordon J. Freeman, Wenyi Wei
Summary: The protein arginine methyltransferase PRMT1 suppresses the anti-tumor immune response by methylating cGAS and preventing its dimerization. Inhibition of PRMT1 activates the cGAS/STING-dependent DNA sensing signaling and increases the expression of interferon response genes, tumor-infiltrating lymphocytes, and tumoral PD-L1. Combination therapy of PRMT1 inhibitor with anti-PD-1 antibody enhances the anti-tumor therapeutic efficacy.
NATURE COMMUNICATIONS
(2023)
Article
Medicine, Research & Experimental
Satomi Ando, Charles M. Perkins, Yamato Sajiki, Chase Chastain, Rajesh M. Valanparambil, Andreas Wieland, William H. Hudson, Masao Hashimoto, Suresh S. Ramalingam, Gordon J. Freeman, Rafi Ahmed, Koichi Araki
Summary: T cell exhaustion is associated with dysfunction and expression of PD-1. mTOR inhibition during the expansion phase enhances T cell response, while inhibition after exhaustion progresses causes immunosuppression with decreased TIM3(+) cells and increased viral load. mTOR signaling is essential for differentiation of stem-like T cells into TIM3(+) cells.
JOURNAL OF CLINICAL INVESTIGATION
(2023)
