Duhen et al. report that coexpression of PD-1 and ICOS on tumor-infiltrating CD4+ T helper cells enriches for tumor-reactive cells in patients with head and neck squamous cell carcinoma and colorectal cancer. The cover image shows multiplex immunohistochemistry for CD3 (green), CD8 (magenta), FOXP3 (white), ICOS (red), MHC class II (yellow), and cytokeratin (cyan) from a section of a head and neck squamous cell carcinoma.
Targeted protein degradation is a rapidly advancing and expanding therapeutic approach. Drugs that degrade GSPT1 via the CRL4CRBN ubiquitin ligase are a new class of cancer therapy in active clinical development with evidence of activity against acute myeloid leukemia in early phase trials. However, other than activation of the integrated stress response, the downstream effects of GSPT1 degradation leading to cell death are largely undefined, and no murine models are available to study these agents. We identified the domains of GSPT1 essential for cell survival and show that GSPT1 degradation leads to impaired translation termination, activation of the integrated stress response pathway, and TP53-independent cell death. CRISPR-Cas9 screens implicated decreased translation initiation as protective to GSPT1 degradation, suggesting that cells with higher levels of translation are more susceptible to GSPT1 degradation. We defined two Crbn amino acids that prevent Gspt1 degradation in mice, generated a knock-in mouse with alteration of these residues, and demonstrated the efficacy of GSPT1-degrading drugs in vivo with relative sparing of numbers and function of long-term hematopoietic stem cells. Our results provide a mechanistic basis for the use of GSPT1 degraders for the treatment of cancer, including TP53-mutant AML.
Rob S. Sellar, Adam S. Sperling, Mikołaj Słabicki, Jessica A. Gasser, Marie E. McConkey, Katherine A. Donovan, Nada Mageed, Dylan N. Adams, Charles Zou, Peter G. Miller, Ravi Kumar Dutta, Steffen Boettcher, Amy E. Lin, Brittany E. Sandoval, Vanessa A. Quevedo Barrios, Veronica Shkolnik, Jonas Koeppel, Elizabeth K. Henderson, Emma C. Fink, Lu Yang, Anthony K.N. Chan, Sheela Pangeni Pokharel, Erik J. Bergstrom, Rajan Burt, Namrata D. Udeshi, Steven A. Carr, Eric S. Fischer, Chun-Wei Chen, Benjamin L. Ebert
Human cytomegalovirus (HCMV) is the most common congenital infection and a leading cause of stillbirth, neurodevelopmental impairment, and pediatric hearing loss worldwide. Development of a maternal vaccine or therapeutic to prevent congenital HCMV has been hindered by limited knowledge of the immune responses that protect against HCMV transmission in utero. To identify protective antibody responses, we measured HCMV-specific IgG binding and anti-viral functions in paired maternal and cord blood sera from HCMV seropositive transmitting (n=41) and non-transmitting (n=40) mother-infant dyads identified via a large U.S.-based public cord blood bank. We found that high avidity IgG binding to HCMV and antibody-dependent cellular phagocytosis (ADCP) were associated with reduced risk of congenital HCMV infection. We also determined that HCMV-specific IgG activation of FcγRI and FcγRII was enhanced in non-transmitting dyads and that increased ADCP responses were mediated through both FcγRI and FcγRIIA expressed on human monocytes. These findings suggest that engagement of FcγRI/FcγRIIA and Fc effector functions including ADCP may protect against congenital HCMV infection. Taken together, these data can guide future prospective studies on immune correlates against cCMV transmission and inform HCMV vaccine and immunotherapeutic development.
Eleanor C. Semmes, Itzayana G. Miller, Courtney E. Wimberly, Caroline T. Phan, Jennifer A. Jenks, Melissa J. Harnois, Stella J. Berendam, Helen Webster, Jillian H. Hurst, Joanne Kurtzberg, Genevieve G. Fouda, Kyle M. Walsh, Sallie R. Permar
Vascular endothelial growth factor C (VEGF-C) induces lymphangiogenesis via VEGF receptor-3 (VEGFR3), encoded by the most frequently mutated gene in human primary lymphedema. Angiopoietins (Angs) and their Tie receptors regulate lymphatic vessel development and mutations of the ANGPT2 gene were recently found in human primary lymphedema. However, the mechanistic basis of Ang2 activity in lymphangiogenesis is not fully understood. Here we used gene deletion, blocking antibodies, transgene induction and gene transfer to study how Ang2, its Tie2 receptor and Tie1 regulate lymphatic vessels. We discovered that VEGF-C-induced Ang2 secretion from lymphatic endothelial cells (LECs) is involved in full Akt activation downstream of phosphoinositide-3 kinase (PI3K). Neonatal deletion of genes encoding the Tie receptors or Ang2 in LECs, or administration of Ang2 blocking antibody decreased VEGFR3 presentation on LECs and inhibited lymphangiogenesis. A similar effect was observed in LECs upon deletion of PI3K catalytic p110α subunit or with small molecule inhibition of a constitutively active PI3K located downstream of Ang2. Deletion of Tie receptors or blockade of Ang2 decreased VEGF-C-induced lymphangiogenesis also in adult mice. Our results reveal important crosstalk between the VEGF-C and Ang signaling pathways and suggest new avenues for therapeutic manipulation of lymphangiogenesis by targeting Ang2-Tie-PI3K signaling.
Emilia A. Korhonen, Aino Murtomäki, Sawan Kumar Jha, Andrey Anisimov, Anne Pink, Yan Zhang, Simon Stritt, Inam Liaqat, Lukas Stanczuk, Laura Alderfer, Zhiliang Sun, Emmi Kapiainen, Abhishek Singh, Ibrahim Sultan, Anni Lantta, Veli-Matti Leppänen, Lauri Eklund, Yulong He, Hellmut G. Augustin, Kari Vaahtomeri, Pipsa Saharinen, Taija Mäkinen, Kari Alitalo
BACKGROUND. Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) has achieved remarkable clinical efficacy in metastatic cancers such as melanoma and cervical cancer (CC). Here we explored the safety, feasibility and preliminary tumor response and performed translational investigations of adjuvant immunotherapy using infusion of autogenous (auto)-TILs following concurrent chemoradiotherapy (CCRT) in CC patients with locally advanced disease. METHODS. Twenty-seven CC patients with stage III to IV disease were recruited in this single-center, phase I study. TILs were isolated from lesions in the uterine cervix and generated under good manufacturing practices (GMP) conditions and then infused after CCRT plus intramuscular interleukin (IL)-2 injections. RESTULTS. From 27 patients, TILs were successfully expanded from 20 patients, with a feasibility of 74.1%. Twelve patients received TILs following CCRT. Adverse events (AEs) were primarily attributable to CCRT. Only 1 (8.3%) patient experienced severe toxicity with a grade 3 hypersensitivity reaction after TIL infusion. No autoimmune AEs, such as pneumonitis, hepatitis, or myocarditis, occurred, and there was no treatment-related mortality. Nine of 12 patients (75.0%) attained complete response, with a disease control duration of 9 to 22 months. Translational investigation showed that the transcriptomic characteristics of the infused TIL products and some immune biomarkers in the tumor microenvironment and serum of CC patients at baseline were correlated with the clinical response. CONCULSION. TIL-based ACT following CCRT was safe in an academic center setting, with potential effective responses in locally advanced CC patients. ‘Hot’ inflammatory immune environments are beneficial to the clinical efficacy of TIL-based ACT as adjuvant therapy. TRIAL REGISTRATION. ClinicalTrials.gov NCT04443296. FUNDING. Natinoal Key R&D Program: Sci-Tech Key Program of the Guangzhou City Science Foundation; the Guangdong Provinve Sci-Tech International Key Program; the National Natural Science Foundation of China.
He Huang, Caiping Nie, Xiu-feng Liu, Bin Song, Jian-hui Yue, Jingxiao Xu, Jia He, Kui Li, Yan-ling Feng, Ting Wan, Min Zheng, Yanna Zhang, Wei-jun Ye, Jun-dong Li, Yan-fang Li, Jun-yun Li, Xin-Ping Cao, Zhi-min Liu, Xiao-Shi Zhang, Qing Liu, Xi Zhang, Ji-Hong Liu, Jiang Li
Background: Head and neck squamous cell carcinoma not associated with human papillomavirus (HPV-unrelated HNSCC) is associated with high rates of recurrence and poor survival. Methods: We conducted a clinical trial in 14 patients with newly diagnosed, HPV-unrelated HNSCC to evaluate the safety and efficacy of neoadjuvant bintrafusp alfa, a bifunctional fusion protein that blocks programmed death-ligand 1 (PD-L1) and neutralizes transforming growth factor-beta (TGF-). Results: Bintrafusp alfa was well tolerated, and no treatment-associated surgical delays or complications occurred. Objective pathologic responses were observed and 12 of 14 patients (86%) were alive and disease free at one year. Alterations in regulatory T cell infiltration and spatial distribution relative to proliferating CD8 T cells indicated reversal of Treg immunosuppression in the primary tumor. Detection of neoepitope-specific tumor T cell responses, but not viral-specific responses, correlated with development of a pathologic response. Detection of neoepitope-specific responses and pathologic responses in tumors was not correlated with genomic features or tumor antigenicity but was associated with reduced pre-treatment myeloid cell tumor infiltration. These results indicate that dual PD-L1 and TGF- blockade can safely enhance tumor antigen-specific immunity and highlight the feasibility of multi-mechanism neoadjuvant immunotherapy in patients with HPV-unrelated HNSCC. Conclusion: Our studies provide new insight into the ability of neoadjuvant immunotherapy to induce polyclonal neoadjuvant-specific T cell responses in tumors and suggest that features of the tumor microenvironment, such as myeloid cell infiltration, may be a major determinant of enhanced anti-tumor immunity following such treatment.
Jason M. Redman, Jay Friedman, Yvette Robbins, Cem Sievers, Xinping Yang, Wiem Lassoued, Andrew Sinkoe, Antonios Papanicolau-Sengos, Chyi-Chia R. Lee, Jennifer L. Marte, Evrim B. Turkbey, Wojciech Mydlarz, Arjun S. Joshi, Nyall R. London, Jr., Matthew Pierce, Rodney J. Taylor, Steven Hong, Andrew Nguyen, Patrick Soon-Shiong, Jeffrey Schlom, James L. Gulley, Clint T. Allen
JCI This Month is a digest of the research, reviews, and other features published each month.
Next-generation sequencing (NGS) technology enables rapid, high-throughput sequencing of thousands of genes or even entire genomes. The speed and scale of these techniques makes them powerful tools in medicine, creating an opportunity to build and search deep genetic databases, refine diagnoses, and inform precision medicine approaches. In this series, designed by Ben H. Park, five reviews describe how NGS is revolutionizing clinical insights into disease. Wensel et al. compare key NGS methods for investigating the microbiome, emphasizing the need for careful study design and validation as these techniques become more widely adopted. Schuler et al. outline the capabilities and limitations of current genetic testing approaches and provide examples of clinical scenarios in which NGS was combined with other strategies to make a diagnosis. The contribution from Waarts et al. describes how NGS has contributed to the identification of targetable mutations in a range of cancers and discusses challenges to achieving maximal therapeutic benefit of targeted treatments. Halima et al. focus on high-throughput NGS approaches that are revealing the fundamental genetic processes that govern immunity, influencing how we design and implement cancer immunotherapy. Finally, Dang and Park’s review on circulating tumor DNA discusses the advantages of blood-based diagnosis as well as strategies to overcome technical limitations and improve detection of cancer in its earliest stages.