Searching for Extremely Blue UV Continuum Slopes at z=7−11z=7-11 in JWST/NIRCam Imaging: Implications for Stellar Metallicity and Ionizing Photon Escape in Early Galaxies

The ultraviolet (UV) continuum slope ($\beta$ where f$_\lambda\propto \lambda^\beta$) of galaxies is sensitive to a variety of properties, from the metallicity and age of the stellar population to the attenuation from dust through the galaxy. Considerable attention has focused on identifying reionization-era galaxies with very blue UV slopes ($\beta<-3$). Not only do such systems provide a signpost of low metallicity stars, but they also identify galaxies that likely have ionizing photons leaking from their HII regions as such blue UV slopes can only be seen if the reddening effect of nebular continuum has been diminished. In this paper we present a search for reionization-era galaxies with very blue UV colors in recent JWST/NIRCam imaging of the EGS field. We characterize UV slopes for a large sample of $z\simeq 7-11$ galaxies, finding a median value of $\beta =-2.1$. Three of the lower luminosity (M$_{\rm{UV}}\simeq -19.5$) and lower stellar mass (5-6$\times10^7$M$_\odot$) systems exhibit both extremely blue UV slopes ($\beta=-3.1$ to $-3.2$) and rest-optical photometry indicating weak nebular line emission. Each system is very compact (r$_e<$260 pc) with very high star formation rate surface densities. We model the SEDs with a suite of BEAGLE models with varying levels of ionizing photon escape. The SEDs cannot be reproduced with our fiducial (f$_{\rm{esc,HII}}$=0) or alpha enhanced (Z$_*<Z_{\rm{ISM}}$) models. The combined blue UV slopes and weak nebular emission are best-fit by models with significant ionizing photon escape from HII regions (f$_{\rm{esc,HII}}$=0.6-0.8) and extremely low metallicity massive stars (Z$_*$=0.01-0.06 Z$_\odot$). The discovery of these galaxies highlights the potential for JWST to identify large numbers of candidate Lyman Continuum leaking galaxies in the reionization era and suggests low metallicity stellar populations may be veryComment: 11 pages, 8 figures, 2 tables; Submitted to Ap

A JWST/NIRCam Study of Key Contributors to Reionization: The Star-forming and Ionizing Properties of UV-faint z∼7−8z\sim7-8 Galaxies

Spitzer/IRAC imaging has revealed that the brightest $z\sim7-8$ galaxies often exhibit young ages and strong nebular line emission, hinting at high ionizing efficiency among early galaxies. However, IRAC's limited sensitivity has long hindered efforts to study the fainter, more numerous population often thought largely responsible for reionization. Here we use CEERS JWST/NIRCam data to characterize 116 UV-faint (median M$_{UV}=-19.5$) $z\sim6.5-8$ galaxies. The SEDs are typically dominated by young ($\sim$10-50 Myr), low-mass ($M_\ast\sim10^8\ M_\odot$) stellar populations, and we find no need for extremely high stellar masses ($\sim10^{11} M_\odot$). Considering previous studies of UV-bright (M$_{UV}\sim-22$) $z\sim7-8$ galaxies, we find evidence for a strong (5-10$\times$) increase in specific star formation rate toward lower luminosities (median sSFR=103 Gyr$^{-1}$ in CEERS). The larger sSFRs imply a more dominant contribution from OB stars in the relatively numerous UV-faint population, perhaps suggesting that these galaxies are very efficient ionizing agents (median $\xi_{ion}=10^{25.7}$ erg$^{-1}$ Hz). In spite of their much larger sSFRs, we find no significant increase in [OIII]$+$H$\beta$ EWs towards fainter M$_{UV}$ (median $\approx$780 $\mathring{A}$). If confirmed, this may indicate that a substantial fraction of our CEERS galaxies possess extremely low metallicities ($\lesssim$3% $Z_\odot$) where [OIII] emission is suppressed. Alternatively, high ionizing photon escape fractions or bursty star formation histories can also weaken the nebular lines in a subset of our CEERS galaxies. While the majority of our objects are very blue (median $\beta=-2.0$), we identify a significant tail of very dusty galaxies ($\beta\sim-1$) at $\approx$0.5$L_{UV}^\ast$ which may contribute significantly to the $z\sim7-8$ star formation rate density.Comment: Accepted in MNRAS. Updated to use the most recent NIRCam zeropoints. There are no significant changes to the conclusions relative to v

Transcriptional Activity and Stability of CD39+CD103+CD8+T Cells in Human High-Grade Endometrial Cancer

Tumor-infiltrating CD8+ T cells (TIL) are of the utmost importance in anti-tumor immunity. CD103 defines tumor-resident memory T cells (T-RM cells) associated with improved survival and response to immune checkpoint blockade (ICB) across human tumors. Co-expression of CD39 and CD103 marks tumor-specific T-RM with enhanced cytolytic potential, suggesting that CD39+CD103+ T-RM could be a suitable biomarker for immunotherapy. However, little is known about the transcriptional activity of T-RM cells in situ. We analyzed CD39+CD103+ T-RM cells sorted from human high-grade endometrial cancers (n = 3) using mRNA sequencing. Cells remained untreated or were incubated with PMA/ionomycin (activation), actinomycin D (a platinum-like chemotherapeutic that inhibits transcription), or a combination of the two. Resting CD39+CD103+ T-RM cells were transcriptionally active and expressed a characteristic T-RM signature. Activated CD39+CD103+ T-RM cells differentially expressed PLEK, TWNK, and FOS, and cytokine genes IFNG, TNF, IL2, CSF2 (GM-CSF), and IL21. Findings were confirmed using qPCR and cytokine production was validated by flow cytometry of cytotoxic TIL. We studied transcript stability and found that PMA-responsive genes and mitochondrial genes were particularly stable. In conclusion, CD39+CD103+ T-RM cells are transcriptionally active T-RM cells with a polyfunctional, reactivation-responsive repertoire. Secondly, we hypothesize that differential regulation of transcript stability potentiates rapid responses upon T-RM reactivation in tumors

L1CAM expression in uterine carcinosarcoma is limited to the epithelial component and may be involved in epithelial–mesenchymal transition

Uterine carcinosarcoma (UCS) has been proposed as a model for epithelial–mesenchymal transition (EMT), a process characterized by a functional change facilitating migration and metastasis in many types of cancer. L1CAMis an adhesion molecule that has been involved in EMT as a marker for mesenchymal phenotype.We examined expression of L1CAM in UCS in a cohort of 90 cases from four different centers. Slides were immunohistochemically stained for L1CAMand scored in four categories (0%, 50%). A score of more than 10% was considered positive for L1CAM. The median age at presentation was 68.6 years, and half of the patients (53.3%) presented with FIGO stage 1 disease. Membranous L1CAM expression was positive in the epithelial component in 65.4% of cases. Remarkably, expression was negative in the mesenchymal component. In cases where both components were intermingled, expression limited to the epithelial component was confirmed by a double stain for L1CAMand keratin. Expression of L1CAMdid not relate to overall or disease-free survival. Our findings suggest L1CAMis either not a marker for the mesenchymal phenotype in EMT, or UCS is not a good model for EMT

Combined STING levels and CD103+ T cell infiltration have significant prognostic implications for patients with cervical cancer

Activation of STimulator of INterferon Genes (STING) is important for induction of anti-tumor immunity. A dysfunctional STING pathway is observed in multiple cancer types and associates with poor prognosis and inferior response to immunotherapy. However, the association between STING and prognosis in virally induced cancers such as HPV-positive cervical cancer remains unknown. Here, we investigated the prognostic value of STING protein levels in cervical cancer using tumor tissue microarrays of two patient groups, primarily treated with surgery (n = 251) or radio(chemo)therapy (n = 255). We also studied CD103, an integrin that marks tumor-reactive cytotoxic T cells that reside in tumor epithelium and that is reported to associate with improved prognosis. Notably, we found that a high level of STING protein was an independent prognostic factor for improved survival in both the surgery and radio(chemo)therapy group. High infiltration of CD103+ T cells was associated with improved survival in the radio(chemo)therapy group. The combination of STING levels and CD103+ T cell infiltration is strongly associated with improved prognosis. We conclude that combining the prognostic values of STING and CD103 may improve the risk stratification of cervical cancer patients, independent from established clinical prognostic parameters

L1CAM expression in uterine carcinosarcoma is limited to the epithelial component and may be involved in epithelial-mesenchymal transition

Uterine carcinosarcoma (UCS) has been proposed as a model for epithelial-mesenchymal transition (EMT), a process characterized by a functional change facilitating migration and metastasis in many types of cancer. L1CAM is an adhesion molecule that has been involved in EMT as a marker for mesenchymal phenotype. We examined expression of L1CAM in UCS in a cohort of 90 cases from four different centers. Slides were immunohistochemically stained for L1CAM and scored in four categories (0%, 50%). A score of more than 10% was considered positive for L1CAM. The median age at presentation was 68.6years, and half of the patients (53.3%) presented with FIGO stage 1 disease. Membranous L1CAM expression was positive in the epithelial component in 65.4% of cases. Remarkably, expression was negative in the mesenchymal component. In cases where both components were intermingled, expression limited to the epithelial component was confirmed by a double stain for L1CAM and keratin. Expression of L1CAM did not relate to overall or disease-free survival. Our findings suggest L1CAM is either not a marker for the mesenchymal phenotype in EMT, or UCS is not a good model for EMT

Association of homozygous variants of STING1 with outcome in human cervical cancer

DNA-sensing receptor Cyclic GMP-AMP Synthase (cGAS) and its downstream signaling effector STimulator of INterferon Genes (STING) have gained significant interest in the field of tumor immunology, as a dysfunctional cGAS-STING pathway is associated with poor prognosis and worse response to immunotherapy. However, studies so far have not taken into account the polymorphic nature of the STING-encoding STING1 gene. We hypothesized that the presence of allelic variance in STING1 would cause variation between individuals as to their susceptibility to cancer development, cancer progression, and potential response to (immuno)therapy. To start to address this, we defined the genetic landscapes of STING1 in cervical scrapings and investigated their corresponding clinical characteristics across a unique cohort of cervical cancer patients and compared them with independent control cohorts. Although we did not observe an enrichment of particular STING1 allelic variants in cervical cancer patients, we did find that the occurrence of homozygous variants HAQ/HAQ and R232H/R232H of STING1 were associated with both younger age of diagnosis and higher recurrence rate. These findings were accompanied by worse survival, despite comparable mRNA and protein levels of STING and numbers of infiltrated CD8(+) T cells. Our findings suggest that patients with HAQ/HAQ and R232H/R232H genotypes may have a dysfunctional cGAS-STING pathway that fails to promote efficient anticancer immunity. Interestingly, the occurrence of these genotypes coincided with homozygous presence of the V48V variant, which was found to be individually associated with worse outcome. Therefore, we propose V48V to be further evaluated as a novel prognostic marker for cervical cancer

Expression of CD39 Identifies Activated Intratumoral CD8+T Cells in Mismatch Repair Deficient Endometrial Cancer

Identification of human cancer-reactive CD8+ T cells is crucial for the stratification of patients for immunotherapy and determination of immune-therapeutic effects. To date, these T cells have been identified mainly based on cell surface expression of programmed cell death protein 1 (PD-1) or co-expression of CD103 and CD39. A small subset of CD103- CD39+ CD8+ T cells is also present in tumors, but little is known about these T cells. Here, we report that CD103- CD39+ CD8+ T cells from mismatch repair-deficient endometrial tumors are activated and characterized predominantly by expression of TNFRSF9. In vitro, transforming growth factor-beta (TGF-beta) drives the disappearance of this subset, likely through the conversion of CD103- CD39+ cells to a CD103+ phenotype. On the transcriptomic level, T cell activation and induction of CD39 was associated with a number of tissue residence and TGF-beta responsive transcription factors. Altogether, our data suggest CD39+ CD103- CD8+ tumor-infiltrating T cells are recently activated and likely rapidly differentiate towards tissue residence upon exposure to TGF-beta in the tumor micro-environment, explaining their relative paucity in human tumors

Prognostic image-based quantification of CD8CD103 T cell subsets in high-grade serous ovarian cancer patients

CD103-positive tissue resident memory-like CD8+ T cells (CD8CD103 TRM) are associated with improved prognosis across malignancies, including high-grade serous ovarian cancer (HGSOC). However, whether quantification of CD8, CD103 or both is required to improve existing survival prediction and whether all HGSOC patients or only specific subgroups of patients benefit from infiltration, remains unclear. To address this question, we applied image-based quantification of CD8 and CD103 multiplex immunohistochemistry in the intratumoral and stromal compartments of 268 advanced-stage HGSOC patients from two independent clinical institutions. Infiltration of CD8CD103 immune cell subsets was independent of clinicopathological factors. Our results suggest CD8CD103 TRM quantification as a superior method for prognostication compared to single CD8 or CD103 quantification. A survival benefit of CD8CD103 TRM was observed only in patients treated with primary cytoreductive surgery. Moreover, survival benefit in this group was limited to patients with no macroscopic tumor lesions after surgery. This approach provides novel insights into prognostic stratification of HGSOC patients and may contribute to personalized treatment strategies in the future