Spontaneous Spread Research Articles

First record of <i>Pancratium maritimum</i> L. (Amaryllidaceae) for the Friuli Venezia Giulia region, Italy

We report the first observation of the psammophyte plant species Pancratium maritimum L. (Amaryllidaceae) in the Friuli Venezia Giulia region, Italy. Four adult individuals were observed in spring 2023 on the residual dunes of Lignano Sabbiadoro municipality behind a beach resort. Although we lack genetic analysis to determine its provenance, considering the absence of locally cultivated individuals and the expansion of the species in the neighboring region of Veneto, with individuals located ca. 20 km from this reported observation, we believe that its arrival in Friuli Venezia Giulia should be considered a spontaneous spread of a new native species for the region. This finding indicates that the species now has a distribution extending along the entire Italian coastline.

A spontaneous spread of black locust (Robinia pseudoacacia L.): the importance of seed and vegetative reproduction

Abstract The importance of seed and vegetative propagation for the spontaneous expansion of black locust on abandoned agricultural land was evaluated in the present study. The dynamics of expansion was reconstructed on the basis of spatial distribution data on the age of individuals of this species. A non-homogeneous Poisson process with a linear trend and a Widom-Rowlinson model were the most appropriate in explaining the spatial distribution of R. pseudoacacia individuals. The negative linear trend was statistically significant for the vast majority of polygons in the area of spontaneous expansion of R. pseudoacacia, but insignificant in the artificial plantation. The model parameter η indicates the aggregated spatial distribution of R. pseudoacacia in the zone of spontaneous spread due to the vegetative mechanism of spread. The distribution of R. pseudoacacia in the artificial tree plantation was close to regular, or either random or aggregated. In the early stages, the seed reproduction is the most likely process of R. pseudoacacia spreading. The seed mechanism of spreading follows a spatial pattern, which is explained by a linear trend. The next stage is a combination of both seed and vegetative mechanisms of spread, which also lasts about 4–5 years. At the last stage, the spread occurs mainly through the vegetative mechanism, and the rate of spread of the community slows down significantly. The trigger for the spread is anthropogenic impact.

Differential cortical layer engagement during seizure initiation and spread in humans

Despite decades of research, we still do not understand how spontaneous human seizures start and spread – especially at the level of neuronal microcircuits. In this study, we used laminar arrays of micro-electrodes to simultaneously record the local field potentials and multi-unit neural activities across the six layers of the neocortex during focal seizures in humans. We found that, within the ictal onset zone, the discharges generated during a seizure consisted of current sinks and sources only within the infra-granular and granular layers. Outside of the seizure onset zone, ictal discharges reflected current flow in the supra-granular layers. Interestingly, these patterns of current flow evolved during the course of the seizure – especially outside the seizure onset zone where superficial sinks and sources extended into the deeper layers. Based on these observations, a framework describing cortical-cortical dynamics of seizures is proposed with implications for seizure localization, surgical targeting, and neuromodulation techniques to block the generation and propagation of seizures.

Ecological–Coenotic features and Current Distribution Echinocystis lobata (Michx.) Torr. et A. Gray (Cucurbitaceae) in Ukraine

Abstract The information on the spontaneous spread (1152 localities) of the invasive species Echinocystis lobata is summarized. It was found that this alien species is timed to coastal water biotopes, floodplain meadows, mesophytic forests, wetlands, as well as disturbed ecotopes. The syntaxonomic scheme of vegetation with the participation of E. lobata includes 13 classes, 7 orders, 8 alliances, and 8 associations. It is predicted that under the conditions of a temperature increase of 3 °C, there will likely be changes in the carbonate content (Ca), water regime (Hd) of the soil, thermal regime (Tm), and climate humidity (Om), which will cause a reduction in the secondary range of the species in Ukraine, and the changed acid regime of the soil will cause (Rc) its disappearance in some localities. The obtained data can be used to carry out preventive measures regarding the emergence and further distribution of E. lobata in new habitats with different degrees of anthropogenic transformation.

Urban hedges facilitate spontaneous woody plants

Most trees and other woody plants growing within urban areas are deliberately cultivated native or non-native plants. Opportunities for spontaneous establishment and spread of woody species are scarce in an urban environment, especially if the establishment begins from seeds. We hypothesized that urban hedges might offer safe sites for the spontaneous establishment of woody plants, which reach the hedges through propagule dispersal. We recorded the species composition of urban hedges in Maribor (NE Slovenia) in a gradient from the city centre outwards and evaluated the species’ invasive potential and ecological requirements, along with hedge characteristics. Results show that hedges facilitated the survival and growth of 69 woody plants from 28 families. Among these, 62% were non-native and 10% were locally invasive. Most of recorded non-native woody plants were ornamentals. Moreover, for native species, we show that the stressful, warmer urban environment mostly facilitates the establishment of species in the genera Hedera and Acer. Comparison of non-native and native plants showed the former are more drought and heat tolerant than the latter. We further show that with distance from the city centre, the number of bird-dispersed species increases, in contrast to the wind-dispersed species. Additionally, our results suggest evergreen hedges may be less permeable to wind-dispersed propagules than deciduous hedges. Next, we stress the importance of paved surfaces and urbanization, selecting for the thermophile, drought tolerant, wind-dispersed woody plants that find refuge in urban hedges. Our results suggest urban hedges can facilitate the establishment of a wide range of woody plant species.

Explosive household spread of the SARS-CoV-2 Omicron variant in China in late 2022

Immediately after easing the 3-year zero-COVID policy in mainland China, an explosive spread of the Omicron variant of SARS-CoV-2 occurred in late 2022, despite most people staying at home. We characterise the virus transmission within households and the associated risk factors. We conducted an online survey, which was done by professors and postgraduate students in the discipline of building environment and energy engineering, and all questionnaires were completed on December 31, 2022 and collected over a period of 11 h. The self-reported infection status of 12,037 people in 4421 households was collected in mainland China. Data on vaccination status, mask wearing, hand hygiene, ventilation, and bathroom air odours were analysed. Of the surveyed population, 79.2% (9533/12,037) reported infection based on symptoms or rapid test results by 31 December. The daily number of cases peaked on 20 December nationally and between 16 and 26 December in different provinces. Better ventilation in shared corridors and living rooms was associated with a lower household daily incidence rate and a lower fever occurrence. Residing on upper floors was associated with a higher daily incidence rate. Wearing an N95 respirator when leaving home could effectively reduce household infection risk. The observed similarity in the peak infection rate and its date of occurrence in different provincial regions suggest the spontaneous and simultaneous spread of the Omicron variant across the country. Crowded households, poor ventilation in shared common corridors, and residing on upper floors were associated with a higher incidence and more symptoms of disease.

First-in-Class Humanized Antibody against Alternatively Spliced Tissue Factor Augments Anti-Metastatic Efficacy of Chemotherapy in a Preclinical Model of Pancreatic Ductal Adenocarcinoma.

Alternatively spliced tissue factor (asTF) promotes the progression of pancreatic ductal adenocarcinoma (PDAC) by activating β1-integrins on PDAC cell surfaces. hRabMab1, a first-in-class humanized inhibitory anti-asTF antibody we recently developed, can suppress PDAC primary tumor growth as a single agent. Whether hRabMab1 has the potential to suppress metastases in PDAC is unknown. Following in vivo screening of three asTF-proficient human PDAC cell lines, we chose to make use of KRAS G12V-mutant human PDAC cell line PaCa-44, which yields aggressive primary orthotopic tumors with spontaneous spread to PDAC-relevant anatomical sites, along with concomitant severe leukocytosis. The experimental design featured orthotopic tumors formed by luciferase labeled PaCa-44 cells; administration of hRabMab1 alone or in combination with gemcitabine/paclitaxel (gem/PTX); and the assessment of the treatment outcomes on the primary tumor tissue as well as systemic spread. When administered alone, hRabMab1 exhibited poor penetration of tumor tissue; however, hRabMab1 was abundant in tumor tissue when co-administered with gem/PTX, which resulted in a significant decrease in tumor cell proliferation; leukocyte infiltration; and neovascularization. Gem/PTX alone reduced primary tumor volume, but not metastatic spread; only the combination of hRabMab1 and gem/PTX significantly reduced metastatic spread. RNA-seq analysis of primary tumors showed that the addition of hRabMab1 to gem/PTX enhanced the downregulation of tubulin binding and microtubule motor activity. In the liver, hRabMab1 reduced liver metastasis as a single agent. Only the combination of hRabMab1 and gem/PTX eliminated tumor cell-induced leukocytosis. We here demonstrate for the first time that hRabMab1 may help suppress metastasis in PDAC. hRabMab1's ability to improve the efficacy of chemotherapy is significant and warrants further investigation.

Radiation-induced cutaneous vasculopathy of the breast: a rare case report

BackgroundRadiation therapy is often indicated as part of the treatment for breast cancer and is therefore used frequently worldwide. Vasculopathy is a general term used to describe any condition that affects blood vessels. We present a case report of a patient who presented with vasculopathy as a rare late side effect of radiation therapy to the breast.Case presentationThis 66-year-old woman was initially treated with breast-conserving surgery for early-stage receptor-positive left breast carcinoma. She received postoperative radiation therapy and hormonal treatment with tamoxifen. She developed sudden spontaneous painless ecchymosis spread over the whole irradiated area 1.5 years after finishing her radiation therapy. Tumor relapse was excluded. There was no associated vasculitis. The cause was presumed to be multifactorial. She had a history of smoking and was known to have hyperlipidemia. She had undergone several surgical treatments at the left breast one year after her initial breast-conserving treatment and was taking tamoxifen. Anti-inflammatory medicine and treatments increasing local blood flow were prescribed. The ecchymosis resolved completely within one month.ConclusionsVasculopathy can occur as a rare late side effect of radiation therapy. It can be reversible. Prevention begins with carefully treating precipitating factors.

Fragmentation and biodiversity change in urban vegetation: A case study of tram lines

AbstractThis study explores the vegetation composition along various tram line sections in Bydgoszcz, Poland, with a focus on understanding the impact of usage, maintenance, and historical development on urban vegetation dynamics. This study addresses this knowledge gap by investigating how these factors influence plant species composition, leading to variations in the prevalence of native and non‐native species. The aim of this study is to contribute to urban ecological knowledge and inform vegetation management strategies. The investigation centers on five tram line sites representing different usage and maintenance scenarios: Unused line, New line, Loop rec, Loop old, and Old line. Through phytocoenological relevés conducted in 2020 and 2021, we measured the plant taxa coverage. Detrended Correspondence Analysis (DCA) and Canonical Correspondence Analysis (CCA) revealed relationships between plant species and tram line sites. The results indicated the presence of 107 plant taxa, with graphical representations highlighting the prevalent species on each tram line section. Older sections showed a higher representation of non‐native plant species, whereas new sections exhibited native species dominance. Moisture‐indicative values suggest an affinity for soils with average moisture content. CCA provides insights into the relationships between plant taxa and site variants and offers valuable implications for urban vegetation management and conservation strategies. The novelty of this study lies in its holistic approach for understanding how multiple factors interact to shape urban vegetation. By illuminating urban ecological dynamics and informing decision‐making processes, this study contributes to urban planning, ecology, and biodiversity conservation. Additionally, this study fills a knowledge gap by providing insights into the unique ecological dynamics and species composition of tram lines in urban environments. Unlike previous research in Central European countries focusing on planted vegetation, this study explored the spontaneous spread of plants and successional patterns along tram lines, enhancing our understanding of the environmental conditions created by tram lines that influence vegetation composition and development.

The Epoch that Did Not Happen. The Poem of the Perished and Its Relationship to History

It is difficult to exclude the expression of socialist realism in Lithuanian literature because of a deep coup d’état of intellectual values caused after the Soviets occupied Lithuania in 1940, in a System collapsing and masking political facts. Then, a year later, when the German occupation started, all the horrors of the Soviet occupation revealed their reality, the grip of censorship fell, and a call to the nation began... At that time, Vincas Mykolaitis-Putinas (1893-1967) created a poem which would become a great historical exception from the poetry of the Soviet era, which, after the return of the Red Army in 1944 “folded its wings” against propaganda and censorship legitimising the occupation, and against the introduction of the dogma of socialist realism in literature. The fate of Putinas’ poem became exceptional, breaking destinies by circulating in the underground and remaining anonymous, as the author could not name himself for the sake of survival in literature, spreading from the partisans’ movement to the American Lithuanian press. It is worth taking note of three factors: a) the relevance of the courage of the poem’s insights, which are constantly reborn at the non-end of the story; b) the controversy of the relationship between the poem and the author in the era of “socialist realism” and the uncertainty of that era, which penetrated even the life of a famous writer, fearing the openness of historical truth, c) significance of the creation date of the poem “Vivos plango. Mortuos voco” (1943), its spontaneous spread, concealment of authorship and the circumstances of its returned relevance in the present, which speak of its phenomenon, overshadowing the ineffectiveness of the “socialist realism” introduced by the Soviets in the context of Lithuanian literature.

Marangoni Bursting: Insight into the Role of the Thermocapillary Effect in an Oil Bath

Marangoni bursting describes the spontaneous spread of a droplet of a binary mixture of alcohol/water deposited on a bath of oil, followed by its fast spontaneous fragmentation into a large number of smaller droplets in a self-similar way. Several papers have aimed to describe the physical phenomena underlying this spectacular phenomenon, in which two opposite effects, solutal and thermal Marangoni stresses, play competitive roles. We performed investigations of the Marangoni bursting phenomenon, paying attention to the surface temperature changes during bursting and after it. Fragmentation instabilities were monitored using a thermal camera for various initial alcohol/water compositions and at different stages of the process. We uncovered the role of thermocapillary Marangoni flows within the more viscous oil phase that are responsible for outward and inward shrinking of the periphery circle at the final stage of the phenomenon, enabling a more comprehensive understanding of the thermal Marangoni effect. Simulations of the Marangoni thermocapillary effect in an oil bath by solving coupled Navier–Stokes and heat transport equations using the COMSOL Multiphysics software platform support our experimental observations.

Analysis of chosen growth and reproductive traits of manna ash (Fraxinus ornus) with regards to its expansive properties

Manna ash (Fraxinus ornus L.) is a Mediterranean shrub or a small tree with the northern limit of its natural range in central Europe. At the same time, it is also a tree species which, due to its considerable tolerance to high temperatures and lack of moisture, as well as some expansive properties, could be expected to increase its range in the coming decades as a result of the changing climate and the associated spontaneous spread. The paper summarizes the results of several years of our research, during which we evaluated the following growth and reproductive characteristics: (1) phenological traits and the length of the growing season, (2) the intensity and evenness of fruiting, and (3) the numbers of individuals and stems according to the height categories. In addition, the species composition of vegetation cover was analysed on the sites with the occurrence of manna ash. Observations were made in two autochthonous populations of manna ash in Southern Slovakia and one allochthonous population in its central region. The onset of spring vegetative and generative phenophases showed a noticeable latitudinal trend during our observations (2015‒2019). In Central Slovakia, flowering and leafing of manna ash occurred on average more than two weeks later than in its southernmost region. The “Central Slovakian” population of manna ash was also characterised by the earliest onset of autumn vegetative phenophases and the lowest total length of the growing season. Despite these trends, flowering and fruiting in this population were relatively regular ‒ in contrast to the other two sites, it was observed every year. In this locality, we also observed the highest total numbers of individuals and stems in all the height categories and the markedly decreased occurrence of competing species. The achieved results point out to the considerable vigour and high reproductive ability of the allochthonous population of manna ash outside its natural range and the natural range of its most important competitors.

Assessing the Spontaneous Spread of Climate-Adapted Woody Plants in an Extensively Maintained Collection Garden.

Climate change may strongly modify the habitat conditions for many woody plant species. Some species could disappear from their natural habitats and become endangered, while others could adapt well to the changed environmental conditions and continue to survive successfully or even proliferate more easily. A similar process can occur within the artificial urban environment as the hitherto popularly planted urban trees may suffer from the extremities of the urban climate. However, among the planted taxa, there are species that spread spontaneously and appear as weeds in extensively managed gardens. In our study, we evaluated the native and non-native species involved in spontaneous spreading in the institutional garden of Buda Arboretum (Budapest) during the COVID-19 period in 2020-2021 when entry was prohibited, and maintenance went on in a restricted, minimal level. We investigated the correlation between spontaneously settling and planted individuals, and then performed multivariate analyses for native and non-native spreading plants for spatial and quantitative data. During our studies, we observed the spontaneous spreading of 114 woody species, of which 38 are native and 76 are non-native. Taking the total number of individuals into account, we found that, in addition to the 2653 woody species planted, a further 7087 spontaneously emerged weeds developed, which creates an additional task in the maintenance.

The Importance of Thermally Abnormal Waters for Bioinvasions—A Case Study of Pistia stratiotes

Thermally abnormal waters represent safe sites for alien invasive plants requiring warmer conditions than provided by the ambient temperatures in the temperate zone. Therefore, such safe sites are frequently inhabited by tropical and sub-tropical plants. By performing a literature review we assessed that at least 55 alien aquatic plant taxa from 21 families were found in thermally abnormal waters in Europe. The majority of these taxa are submerged or rooted macrophytes. Six taxa are listed as quarantine pests according to EPPO. Among these, Pistia stratiotes is present in seven European countries, most of the records of this presence being recent. We studied P. stratiotes in a thermally abnormal stream where a persistent population was able to survive harsh winters. Models showed that the optimum temperature for P. stratiotes biomass was 28.8 ± 3.5 °C. Here, we show that air temperatures had a higher influence on the photosynthetic efficiency of P. stratiotes, estimated by chlorophyll fluorescence measurements, than did water temperatures. Generally, growth, and consequently surface cover for free-floating plants, cannot be explained solely by thermally abnormal water temperatures. We conclude that even though the majority of thermophile alien plant occurrences resulted from deliberate introductions, thermally abnormal waters pose an invasion risk for further deliberate, accidental, or spontaneous spread, which might be more likely for free-floating macrophytes.

Anaerobic Degradation of the Invasive Weed Solidago canadensis L. (goldenrod) and Copper Immobilization by a Community of Sulfate-Reducing and Methane-Producing Bacteria.

The weed Solidago canadensis L. poses a global threat to the environment as it spreads uncontrollably on roadsides, in forests, fields, meadows, and farmland. Goldenrod emits toxic substances that suppress other plants on the site, displacing wild ones. Thus, goldenrod conquers huge areas very quickly. The use of herbicides and mechanical methods does not solve the problem of the spontaneous spread of goldenrod. On the other hand, many scientists consider goldenrod as a valuable source of biologically active substances: flavonoids, phenolic compounds, vitamins, etc. In this study, we consider Solidago plants as a promising, free (cheap), and renewable substrate for the production of methane gas. The goal of the study was to identify the main patterns of degradation of the Solidago canadensis L. plant by methane-producing and sulfate-reducing bacteria with methane gas production and simultaneous detoxification of toxic copper. The composition of the gas phase was monitored by gas chromatography. The pH and redox potential parameters were determined potentiometrically; metal concentrations were measured by photometry. The concentration of flavonoids, sugars and phenolic compounds in plant biomass was determined according to well-known protocols. As a result of the study, high efficiencies of methane degradation in the Solidago plant and copper detoxification were obtained. Methane yield has reached the value of 68.2 L kg-1 TS of Solidago canadensis L. biomass. The degradation coefficient (Kd) was also high at 21.4. The Cu(II) was effectively immobilized by methanogens and sulfate reducers during the goldenrod degradation at the initial concentrations of 500 mg L-1. Thus, a new method of beneficial application of invasive plants was presented. The result confirms the possibility of using methanogenic microorganisms to produce methane gas from invasive weeds and detoxification of toxic metals.

Factors Affecting Plant Composition in Abandoned Railway Areas with Particular Emphasis on Forest Proximity

Abandoned railway areas are places for the spontaneous spread of plants and the formation of specific plant communities. However, only limited information on this subject is available in the literature. The study aimed to determine the direction and the rate of forest formation, taking into account selected environmental factors. A floristic, phytosociological, and soil survey was carried out on a set of abandoned railway lines in the Silesia Province (southern Poland). For this purpose, 30 plots of vegetation were selected: 15 located in the vicinity of forests (F) and 15 surrounded by ruderal or segetal communities (NF). As a result, a total of 132 species (121 vascular plants and 11 mosses) were recorded, including 83 species at F plots and 78 species at NF plots. During the research, 13 syntaxa were distinguished. It was found that silt content, nitrate nitrogen (N-NO3), pH, and phosphorous have a significant impact upon which species dominated in the surveyed areas. It was found that the proximity of the forest was a crucial factor in determining the development of forest communities on abandoned railway areas. These results can be helpful for understanding how environmental conditions shape the forest structure on these types of habitats.

Occurrence of the red-leaved rose Rosa glauca Pourr. (Rosaceae), in Poland

The red-leaved rose, Rosa glauca, has the status of an established, non-invasive kenophyte species in Poland. In the 1970s, it was reported to be commonly cultivated, and since the second half of the 20th century, information about its spontaneous spread, mainly in the western part of the country, has appeared in the literature. The aim of this study was to present the current distribution of Rosa glauca sites in Poland. The possible invasive potential of this species was also studied.

Osteomuscular Hydatidosis

Introduction: Muscular hydatid disease is an extremely rare entity. Intramuscular hydatid cysts are usually secondary, resulting from spontaneous spread of the cysts or after operations for hydatid disease in distant regions. Material and methods: A case of multiple muscular hydatid disease is presented, which behaves like a soft tissue tumor that increases in size, with a review of the pertinent literature. Results: MR images showed a mass in the medial intermuscular septum of the thigh, adjacent and anterior to the femoral vascular bundle. Several satellite lesions are also visualized. The extension study shows another lesion between the right lumbar psoas and the paravertebral muscles in the posterior pararenal space. The diagnosis of hydatid disease is established with CNB. The patient underwent surgery in another center for one of the lesions with poor evolution, finally opting for treatment with Abendazole. Conclusion: In geographical regions where hydatid disease is endemic, the hydatid cyst should be included in the differential diagnosis of a cystic mass in the muscle for its correct treatment.

Abstract 5216: Optimizing antitumor efficacy of granzyme B human fusion constructs targeting the Fn14 antigen in solid tumors. Pre IND pharmacokinetics, schedule, dose optimization and MTD studies

Abstract We previously demonstrated that a human fusion protein construct targeting the Fn14 receptor and containing the cytotoxic granzyme B (GrB) payload (GrB-Fc-IT4) displays impressive in vitro and in vivo cytotoxic effects. Comprehensive mechanism of action studies show that GrB-Fc-IT4 effectively induces cell death in vitro against a broad selection of tumor types with high specificity. The intracellular pathway includes irreversible activation of the caspase cascade and independent mitochondrial depolarization leading to an intense apoptotic cellular damage. This activation occurs quickly and efficiently. Pharmacokinetic studies in mice showed that GrB-Fc-IT4 was cleared bi-exponentially from plasma with a rapid initial clearance (t ½alpha = 0.36 hours) followed by a prolonged terminal-phase plasma half-life (t 1/2beta = 35 hours) similar to that of IgGs. Based on our pharmacokinetic study, we employed a QODX5 therapy schedule and demonstrated impressive antitumor activity against several tumor models including PDX-lung, A459 (NSCLC) and MDA-MB231(TNBC) tumor models. In the present study we compared the in vivo antitumor efficacy of GrB-Fc-IT4 against A549 (NSCLC) tumor cell line, using two different dosing schedules (QODx5 vs QWx5). There was a clear dose and schedule dependence and that treating mice bearing A549 tumors with 32mg/kg/dose using a QOWx5 schedule induced a complete tumor growth inhibition (7/10 tumors regressed) with 3/10 tumors showing no growth up to 50 days after the last dose. Preliminary results suggest that GrB-Fc-IT4 may reduce the formation of spontaneous A549 metastasis into lungs. Further studies are planned to examine the potential of the fusion construct to prevent spontaneous metastatic spread in lung tumor models. Although the fusion construct cross-reacts with the murine Fn14 antigen, maximum tolerated dose studies have confirmed that GrB-Fc-IT4 is a safe product, showing no evidence of toxicity (weight loss) in mice treated with up to 500mg/kg. This suggests that the therapeutic index (TI) for this class of agents is >4. Our data suggest that GrB-Fc-IT4 is a novel class of antitumor agents with a unique mechanism of action. This agent seems to be an exceptionally safe and effective drug and appears to be an ideal candidate for advancing to clinical trials. Research conducted, in part, by Clayton Foundation for Research. Citation Format: Ana Alvarez De Cienfuegos, Lawrence H. Cheung, Khalid A. Mohamedali, Mihai Gagea, Michael G. Rosenblum. Optimizing antitumor efficacy of granzyme B human fusion constructs targeting the Fn14 antigen in solid tumors. Pre IND pharmacokinetics, schedule, dose optimization and MTD studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5216.

Chemotherapy-induced COX-2 upregulation by cancer cells defines their inflammatory properties and limits the efficacy of chemoimmunotherapy combinations

Cytotoxic therapies, besides directly inducing cancer cell death, can stimulate immune-dependent tumor growth control or paradoxically accelerate tumor progression. The underlying mechanisms dictating these opposing outcomes are poorly defined. Here, we show that cytotoxic therapy acutely upregulates cyclooxygenase (COX)-2 expression and prostaglandin E2 (PGE2) production in cancer cells with pre-existing COX-2 activity. Screening a compound library of 1280 approved drugs, we find that all classes of chemotherapy drugs enhance COX-2 transcription whilst arresting cancer cell proliferation. Genetic manipulation of COX-2 expression or its gene promoter region uncover how augmented COX-2/PGE2 activity post-treatment profoundly alters the inflammatory properties of chemotherapy-treated cancer cells in vivo. Pharmacological COX-2 inhibition boosts the efficacy of the combination of chemotherapy and PD-1 blockade. Crucially, in a poorly immunogenic breast cancer model, only the triple therapy unleashes tumor growth control and significantly reduces relapse and spontaneous metastatic spread in an adjuvant setting. Our findings suggest COX-2/PGE2 upregulation by dying cancer cells acts as a major barrier to cytotoxic therapy-driven tumor immunity and uncover a strategy to improve the outcomes of immunotherapy and chemotherapy combinations.