McDonnell, A. M. | bioRxiv Science

bioRxiv2025

Age-dependent tumor-immune interactions underlie immunotherapy response in pediatric cancer

Pediatric cancers originate in rapidly growing tissues within the context of a developing host. However, the interactions between cancer cells and the developing immune system are incompletely understood. Here, we established a suite of pediatric syngeneic mouse cancer models across diverse anatomical sites and compared their tumor immune microenvironment with that in adult mice. Tumors in pediatric mice exhibited significantly accelerated growth and diminished leukocyte infiltration, dominated by naive-like PD-1low/CD8+ T cells, and proliferative MHCIIlow/PD-L1hi/CD86low macrophages. Tumor-infiltrating leukocytes in pediatric mice were enriched for MYC targets, which was also observed in pediatric patient samples. Furthermore, pediatric mice displayed poor responses to anti-PD-1/PD-L1 or bispecific T cell engager antibodies, which could be reversed by inducing a proinflammatory microenvironment via MYC inhibition or inducing macrophage polarization to an MHCIIhi phenotype. These findings underscore the significant influence of young age on cancer immune responses and reveal potential new therapeutic opportunities for pediatric cancers. HIGHLIGHTSO_LIAllograft tumors exhibit markedly accelerated growth in pediatric hosts compared to adults. C_LIO_LITumors growing in pediatric mice have reduced leukocyte infiltration, dominated by naive-like PD-1low/CD8+ T cells, and MHCIIlow/M2-like macrophages. C_LIO_LIEnrichment of MYC target genes is observed in pediatric mouse tumors and confirmed in primary patient tumor samples. C_LIO_LIPediatric mice display reduced response to anti-PD-1/PD-L1 and BiTE immunotherapy, which can be reversed by remodeling the TIME, using either MYC inhibition or macrophage polarization. C_LI

cancer biology↗

bioRxiv2023

Strong and efficient biological carbon pump in the Northern Gulf of Alaska during summer

Sinking marine particles, one pathway of the biological carbon pump, transport carbon to the deep ocean from the oceans surface, thereby contributing to atmospheric carbon dioxide modulation and benthic food supply. Few in situ measurements exist of sinking particles in the Northern Gulf of Alaska (NGA); therefore, regional carbon flux prediction is poorly constrained. In this study, we aim to (1) characterize the magnitude and efficiency of the biological carbon pump and (2) identify drivers of carbon flux in the NGA. We deployed drifting sediment traps to simultaneously collect bulk carbon and intact sinking particles in polyacrylamide gels and measured net primary productivity from deck-board incubations. Through deployments during the summer of 2019, we found high carbon flux magnitude, low attenuation with depth, and high export efficiency. We quantitatively attributed carbon flux between ten particle types, including various fecal pellet categories, dense detritus, and aggregates using polyacrylamide gels. The contribution of aggregates to total carbon flux (41 - 93%) and total carbon flux variability (95%) suggests that aggregation processes, not zooplankton repackaging, played a dominant role in carbon export during the summer of 2019 in the NGA. Furthermore, efficient export correlated significantly with the proportion of chlA > 20 {micro}m, total aggregate flux, and proportion aggregate flux. These results suggest that this stratified, small-cell-dominated ecosystem can have sufficient aggregation to allow for a strong and efficient biological carbon pump. These are the first measurements of carbon flux and the first integrative description of the BCP in this region. Significance StatementO_ST_ABSNovelty and significanceC_ST_ABSWe use a comprehensive approach that brings together sediment trap sampling and imaging, optically measured distribution of sinking and suspended particles, and incubations to make the first description of the biological carbon pump in the Northern Gulf of Alaska. We found high carbon flux magnitude, low attenuation with depth, and high export efficiency with a phytoplankton community consisting of mostly pico-and nanoplankton. Notably, just 25% of carbon flux out of the euphotic zone was as recognizable fecal pellets; instead, we demonstrate that aggregation processes were the main driver of carbon flux. Additionally, size-fractionated chlorophyll-a (> 20 {micro}m) strongly correlated with export efficiency across our region. These results lead us to question our expectations about what conditions and processes can create strong and efficient flux events in the Gulf of Alaska. Breadth of InterestThis study is the first description of the biological carbon pump in the Northern Gulf of Alaska and greatly improves biogeochemical constraints on this system. We report observed primary production, carbon flux, export ratio, carbon flux attenuation, and carbon flux by 10 particle types, which can be used to test regional climate models. This study builds on previous studies published in L&O: Strom et al. 2007; Ebersbach & Trull 2008; McDonnell & Buesseler 2010, 2012; and Durkin et al. 2016. Author contribution statementSO, SS, and AM: conceptualization, methodology, and investigation. SS, AM, GH: funding acquisition and project administration. SO, TK, AM: formal analysis. GH, TK, and AM: supervision. SO: visualization, writing-original draft preparation. SO, GH, TK, SS, and AM: writing-reviewing and editing.

biochemistry↗