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.
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
Epithelial cells lining mucosal surfaces of the gastrointestinal and respiratory tracts uniquely express ERN2/IRE1β, a paralogue of the most evolutionarily conserved endoplasmic reticulum stress sensor ERN1/IRE1α. How ERN2 functions at the host-environment interface and why a second paralogue evolved remain incompletely understood. Using conventionally raised and germ-free Ern2-/- mice, we found that ERN2 was required for microbiota-induced goblet cell maturation and mucus barrier assembly in the colon. This occurred only after colonization of the alimentary tract with normal gut microflora, which induced Ern2 expression. ERN2 acted by splicing Xbp1 mRNA to expand ER function and prevent ER stress in goblet cells. Although ERN1 can also splice Xbp1 mRNA, it did not act redundantly to ERN2 in this context. By regulating assembly of the colon mucus layer, ERN2 further shaped the composition of the gut microbiota. Mice lacking Ern2 had a dysbiotic microbial community that failed to induce goblet cell development and increased susceptibility to colitis when transferred into germ-free wild type mice. These results show that ERN2 evolved at mucosal surfaces to mediate crosstalk between gut microbes and the colonic epithelium required for normal homeostasis and host defense.
Michael J. Grey, Heidi De Luca, Doyle V. Ward, Irini A.M. Kreulen, Katlynn Bugda Gwilt, Sage E. Foley, Jay R. Thiagarajah, Beth A. McCormick, Jerrold R. Turner, Wayne I. Lencer
Acquired resistance is inevitable in non-small cell lung cancers (NSCLCs) treated with osimertinib (OSI), and the mechanisms are not well defined. The MERTK ligand GAS6 promoted downstream oncogenic signaling in EGFR-mutated (EGFRMT) NSCLC cells treated with OSI, suggesting a role for MERTK activation in OSI resistance. Indeed, treatment with MRX-2843, a first-in-class MERTK kinase inhibitor, re-sensitized GAS6-treated NSCLC cells to OSI. Both GAS6 and EGF stimulated downstream PI3K-AKT and MAPK-ERK signaling in parental cells, but only GAS6 activated these pathways in OSI resistant (OSIR) derivative cell lines. Functionally, OSIR cells were more sensitive to MRX-2843 than parental cells, suggesting acquired dependence on MERTK signaling. Furthermore, MERTK and/or its ligands were dramatically upregulated in EGFRMT tumors after treatment with OSI in both xenograft models and patient samples, consistent with induction of autocrine/paracrine MERTK activation. Moreover, treatment with MRX-2843 in combination with OSI, but not OSI alone, provided durable suppression of tumor growth in vivo, even after treatment was stopped. These data identify MERTK as a driver of bypass signaling in treatment-naïve and EGFRMT-OSIR NSCLC cells and predict that MRX-2843 and OSI combination therapy will provide clinical benefit in patients with EGFRMT NSCLC.
Dan Yan, Justus M. Huelse, Dmitri Kireev, Zikang Tan, Luxiao Chen, Subir Goyal, Xiaodong Wang, Stephen V. Frye, Madhusmita Behera, Frank Schneider, Suresh S. Ramalingam, Taofeek K. Owonikoko, H. Shelton Earp, Deborah DeRyckere, Douglas K. Graham
Aberrant expression of viral-like repeat elements is a common feature in epithelial cancers, but the significant diversity of repeat species provides a distinct view of the cancer transcriptome. Repeatome profiling across ovarian, pancreatic, and colorectal cell lines identifies distinct clustering that is independent of tissue of origin that is seen with coding gene analysis. Deeper analysis of ovarian cancer cell lines demonstrated that HSATII satellite repeat expression was highly associated with epithelial mesenchymal transition (EMT) and anti-correlated with interferon (IFN) response genes indicative of a more aggressive phenotype. This relationship of HSATII with high EMT and low IFN response genes was also found in RNA-seq of primary ovarian cancers and associated with significantly shorter survival in a second independent cohort of ovarian cancer patients. Repeat RNAs were also found enriched in tumor derived extracellular vesicles that were capable of stimulating monocyte derived macrophages demonstrating a mechanism of altering the tumor microenvironment with these viral-like sequences. Targeting of HSATII with anti-sense locked nucleic acids (LNAs) stimulated IFN response and induced MHC I expression in ovarian cancer cells lines, highlighting a potential strategy of modulating the repeatome to re-establish anti-tumor cell immune surveillance.
Rebecca L. Porter, Siyu Sun, Micayla N. Flores, Emily Berzolla, Eunae You, Ildiko E. Phillips, Neelima KC, Niyati Desai, Eric C. Tai, Annamaria Szabolcs, Evan R. Lang, Amaya Pankaj, Michael J. Raabe, Vishal Thapar, Katherine H. Xu, Linda T. Nieman, Daniel C. Rabe, David L. Kolin, Elizabeth H. Stover, David Pepin, Shannon L. Stott, Vikram Deshpande, Joyce F. Liu, Alexander Solovyov, Ursula A. Matulonis, Benjamin D. Greenbaum, David T. Ting
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.