Due to advances in sequencing technology, somatically mutated cancer antigens, or neoantigens, are now readily identifiable and have become compelling targets for immunotherapy. In particular, ...neoantigen-targeted vaccines have shown promise in several pre-clinical and clinical studies. However, to date, neoantigen-targeted vaccine studies have involved tumors with exceptionally high mutation burdens. It remains unclear whether neoantigen-targeted vaccines will be broadly applicable to cancers with intermediate to low mutation burdens, such as ovarian cancer. To address this, we assessed whether a derivative of the murine ovarian tumor model ID8 could be targeted with neoantigen vaccines. We performed whole exome and transcriptome sequencing on ID8-G7 cells. We identified 92 somatic mutations, 39 of which were transcribed, missense mutations. For the 17 top predicted MHC class I binding mutations, we immunized mice subcutaneously with synthetic long peptide vaccines encoding the relevant mutation. Seven of 17 vaccines induced robust mutation-specific CD4 and/or CD8 T cell responses. However, none of the vaccines prolonged survival of tumor-bearing mice in either the prophylactic or therapeutic setting. Moreover, none of the neoantigen-specific T cell lines recognized ID8-G7 tumor cells in vitro, indicating that the corresponding mutations did not give rise to bonafide MHC-presented epitopes. Additionally, bioinformatic analysis of The Cancer Genome Atlas data revealed that only 12% (26/220) of HGSC cases had a ≥90% likelihood of harboring at least one authentic, naturally processed and presented neoantigen versus 51% (80/158) of lung cancers. Our findings highlight the limitations of applying neoantigen-targeted vaccines to tumor types with intermediate/low mutation burdens.
Abstract Objective As a negative regulator of T cells, Programmed Death Ligand 1 (PD-L1) is both an indicator and inhibitor of anti -tumor immune responses, which has led to confusion about its ...prognostic significance. We investigated the primary source of PD-L1 expression in epithelial ovarian cancer and its relationship to tumor-infiltrating lymphocytes (TIL) and associated gene products. Methods Tissue microarrays containing high-grade serous carcinomas (HGSC) and endometrioid, clear cell and mucinous ovarian cancers from optimally debulked patients were assessed by immunohistochemistry for expression of PD-L1 and other markers (CD68, CD3, CD8, PD-1, CD103, FoxP3 and CD25). The Cancer Genome Atlas was interrogated for associations between PD-L1 expression and immune-related transcriptional and genomic features of HGSC. Results PD-L1 was primarily expressed by tumor-associated CD68+ macrophages rather than tumor cells. PD-L1+ cells frequently co-localized with CD8, CD4 and PD-1+ TIL, CD25+ FoxP3+ Tregs, and other TIL subsets. PD-L1+ cells were prognostically favorable in HGSC. Moreover, the presence of both PD-L1+ cells and CD8 TIL was associated with better prognosis than CD8 TIL alone. PD-L1 gene expression was independent of BRCA status. At the transcriptional level, PD-L1 was associated with both cytolytic (granzyme B, T-bet and IFN-γ) and suppressive (PD-1, CTLA-4, LAG3 and IDO-1) gene products. Conclusions PD-L1 is primarily expressed by macrophages in ovarian cancer and is strongly associated with both cytolytic and regulatory TIL subsets, resulting in a net positive association with survival. Tumors containing PD-L1+ macrophages appear caught in an immunological stalemate that may require multi-pronged immunotherapy to alleviate.
This book provides an introduction to the study of meaning in human language, from a linguistic perspective. It covers a fairly broad range of topics, including lexical semantics, compositional ...semantics, and pragmatics. The chapters are organized into six units: (1) Foundational concepts; (2) Word meanings; (3) Implicature (including indirect speech acts); (4) Compositional semantics; (5) Modals, conditionals, and causation; (6) Tense & aspect. Most of the chapters include exercises which can be used for class discussion and/or homework assignments, and each chapter contains references for additional reading on the topics covered. As the title indicates, this book is truly an INTRODUCTION: it provides a solid foundation which will prepare students to take more advanced and specialized courses in semantics and/or pragmatics. It is also intended as a reference for fieldworkers doing primary research on under-documented languages, to help them write grammatical descriptions that deal carefully and clearly with semantic issues. The approach adopted here is largely descriptive and non-formal (or, in some places, semi-formal), although some basic logical notation is introduced. The book is written at level which should be appropriate for advanced undergraduate or beginning graduate students. It presupposes some previous coursework in linguistics, but does not presuppose any background in formal logic or set theory.
We show that the in vivo generation of cytokine-producing CD4 T cells specific for a given major histocompatibility class-II (MHCII)-binding peptide of hen egg lysozyme (HEL) is facilitated when mice ...are immunized with splenic antigen presenting cells (APC) pulsed with this HEL peptide and another peptide that binds a different MHCII molecule. This enhanced generation of peptide-specific effector CD4 T cells requires that the same splenic APC be pulsed with both peptides. Pulsed B cells, but not pulsed dendritic cells (DCs), can mediate CD4 T cell cooperation, which can be blocked by disrupting OX40-OX40L (CD134-CD252) interactions. In addition, the generation of HEL peptide-specific CD4 T cell memory is greater when mice are primed with B cells pulsed with the two peptides than with B cells pulsed with the HEL- peptide alone. Based on our findings, we suggest CD4 T cell cooperation is important for vaccine design, underlies the phenomenon of "epitope-spreading" seen in autoimmunity, and that the efficacy of B cell-depletion in the treatment of human cell-mediated autoimmune disease is due to the abrogation of the interactions between autoimmune CD4 T cells that facilitates their activation.
The 2009 Family Smoking Prevention and Tobacco Control Act empowered the U.S. Food and Drug Administration to study "the impact of the use of menthol in cigarettes on the public health, including ...such use among children, African Americans, Hispanics and other racial and ethnic minorities," and develop recommendations. Current scientific evidence comparing human exposures between menthol and nonmenthol smokers shows mixed results. This is largely because of the many differences between commercial menthol and nonmenthol cigarettes other than their menthol content. We conducted an innovative study using two types of test cigarettes: a commercial nonmenthol brand that we mentholated at four different levels, and Camel Crush, a commercial cigarette containing a small capsule in the filter that releases menthol solution into the filter when crushed. Cigarettes were machine-smoked at each of the menthol levels investigated, and the total particulate matter (TPM) was collected on a quartz fiber filter pad and analyzed by gas chromatography/mass spectrometry for menthol, nicotine, tobacco-specific nitrosamines (TSNAs), polycyclic aromatic hydrocarbons (PAHs), cotinine, and quinoline. The mainstream smoke was also monitored continuously in real time on a puff-by-puff basis for seven gas-phase constituents (acetaldehyde, acetonitrile, acrylonitrile, benzene, 1,3-butadiene, isoprene, and 2,5-dimethylfuran), using a proton transfer reaction-mass spectrometer. Average yields (in micrograms/cigarette) for the analytes were determined. Menthol in the TPM samples increased linearly with applied menthol concentration, but the amounts of nicotine along with the target TSNAs, PAHs, cotinine, and quinoline in the cigarettes remained essentially unchanged. Similarly, yields of the targeted volatile organic compounds (VOCs) in whole smoke from the mentholated nonmenthol cigarettes that were measured in real-time were largely unaffected by their menthol levels. In the Camel Crush cigarettes, however, the VOC yields appeared to increase in the presence of menthol, especially in the gas phase. Although we succeeded in characterizing key mainstream smoke constituents in cigarettes that differ only in menthol content, further study is needed to definitively answer whether menthol affects exposure to selected cigarette constituents and thereby influences harm.
This book provides an introduction to the study of meaning in human language, from a linguistic perspective. It covers a fairly broad range of topics, including lexical semantics, compositional ...semantics, and pragmatics. The chapters are organized into six units: (1) Foundational concepts; (2) Word meanings; (3) Implicature (including indirect speech acts); (4) Compositional semantics; (5) Modals, conditionals, and causation; (6) Tense & aspect. Most of the chapters include exercises which can be used for class discussion and/or homework assignments, and each chapter contains references for additional reading on the topics covered. As the title indicates, this book is truly an INTRODUCTION: it provides a solid foundation which will prepare students to take more advanced and specialized courses in semantics and/or pragmatics.
Rice (Oryza sativa L.) is one of the most important food crops worldwide. However, it is also a valuable tool in assessing toxicity of organic and inorganic compounds. For more than 20 years, it has ...been an approved species for standardized phytotoxicity experiments. The objective of this study is to determine germination and radicle (root) and coleoptile (shoot) growth of rice seeds exposed to three insecticides and two herbicides, commonly used in the agricultural production landscape. Although no germination effects of pesticide exposure were observed, significant growth effects were noted between pesticide treatments. Coleoptile growth was significantly (p ≤ 0.05) lowered in metolachlor/atrazine mixture, diazinon, and lambda-cyhalothrin exposures when compared with controls. Radicles of fipronil-exposed seeds were significantly larger (p ≤ 0.05) when compared with controls. This research contributes to the phytotoxicity assessment database, in addition to laying the foundation for the use of rice as a phytoremediation tool for agricultural pesticide runoff.
High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal diversity with widespread but non-random patterns of disease dissemination. We investigated whether local immune ...microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 samples from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across samples and extensive within-patient diversity. Epithelial CD8+ TILs negatively associated with malignant diversity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion.
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•Immune infiltrates vary across space within patients at the time of diagnosis•Immune infiltration shapes malignant cell evolutionary trajectories•T cell clones track with tumor clones across spatial sites within patients•Immune infiltrates and mutational processes show prognostic interactions
Integrated multi-region analysis of metastatic sites in patients with high-grade ovarian cancer highlights the connection between immune microenvironment variation and malignant spread, as well as the combinatorial prognostic value of immune and mutational features.
Some forms of chemotherapy can enhance antitumor immunity through immunogenic cell death, resulting in increased T-cell activation and tumor infiltration. Such effects could potentially sensitize ...tumors to immunotherapies, including checkpoint blockade. We investigated whether platinum- and taxane-based chemotherapy for ovarian cancer induces immunologic changes consistent with this possibility.
Matched pre- and post-neoadjuvant chemotherapy tumor samples from 26 high-grade serous carcinoma (HGSC) patients were analyzed by immunohistochemistry (IHC) for a large panel of immune cells and associated factors. The prognostic significance of post-chemotherapy TIL patterns was assessed in an expanded cohort (
= 90).
Neoadjuvant chemotherapy was associated with increased densities of CD3
, CD8
, CD8
TIA-1
, PD-1
and CD20
TIL. Other immune subsets and factors were unchanged, including CD79a
CD138
plasma cells, CD68
macrophages, and MHC class I on tumor cells. Immunosuppressive cell types were also unchanged, including FoxP3
PD-1
cells (putative regulatory T cells), IDO-1
cells, and PD-L1
cells (both macrophages and tumor cells). Hierarchical clustering revealed three response patterns: (i) TIL
tumors showed increases in multiple immune markers after chemotherapy; (ii) TIL
tumors underwent similar increases, achieving patterns indistinguishable from the first group; and (iii) TIL
cases generally remained negative. Despite the dramatic increases seen in the first two patterns, post-chemotherapy TIL showed limited prognostic significance.
Chemotherapy augments pre-existing TIL responses but fails to relieve major immune-suppressive mechanisms or confer significant prognostic benefit. Our findings provide rationale for multipronged approaches to immunotherapy tailored to the baseline features of the tumor microenvironment.
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