Weather-related disasters are increasing in frequency and severity, leaving survivors to cope with ensuing mental, financial, and physical hardships. This adversity can exacerbate existing morbidities, trigger new ones, and increase the risk of mortality-features that are also characteristic of advanced age-inviting the hypothesis that extreme weather events may accelerate aging. To test this idea, we examined the impact of Hurricane Maria and its aftermath on immune cell gene expression in large, age-matched, cross-sectional samples from free-ranging rhesus macaques (
Variation in social status predicts molecular, physiological and life-history outcomes across a broad range of species, including our own. Experimental studies indicate that some of these relationships persist even when the physical environment is held constant. Here, we draw on datasets from one such study—experimental manipulation of dominance rank in captive female rhesus macaques—to investigate how social status shapes the lived experience of these animals to alter gene regulation, glucocorticoid physiology and mitochondrial DNA phenotypes. We focus specifically on dominance rank-associated dimensions of the social environment, including both competitive and affiliative interactions. Our results show that simple summaries of rank-associated behavioural interactions are often better predictors of molecular and physiological outcomes than dominance rank itself. However, while measures of immune function are best explained by agonism rates, glucocorticoid-related phenotypes tend to be more closely linked to affiliative behaviour. We conclude that dominance rank serves as a useful summary for investigating social environmental effects on downstream outcomes. Nevertheless, the behavioural interactions that define an individual's daily experiences reveal the proximate drivers of social status-related differences and are especially relevant for understanding why individuals who share the same social status sometimes appear physiologically distinct.This article is part of the theme issue ‘The centennial of the pecking order: current state and future prospects for the study of dominance hierarchies’.
DPV-001 is an off-the-shelf biologic containing proteins that are overexpressed by adenocarcinoma and squamous cell cancers. It is enriched for short-lived proteins (SLiPs) and defective ribosomal products (DRiPs), containing canonical and non-canonical alternative cancer neoantigens (dark matter, at least 30 microproteins) in spectrin-coated microvesicles targeted to CLEC9A+ conventional dendritic cells (cDC).1 2 Preclinical models demonstrated enhanced antitumor activity when the murine version of DPV-001 was combined with co-stimulatory agonist(s) and delayed PD-1 blockade(d.PD-1), which formed the basis of the current trial.
Methods
Patients were randomized to receive heterologous prime-boost DPV-001 + sequenced d.PD-1 (retifanlimab Q4W) +/- GITR agonist (INCAGN-1949 Q2W). Tumor biopsies were obtained at baseline, week 2 and week 8, with longitudinal blood and serum sampling. Phenotypic and molecular studies were performed.
Results
18 pts have been treated (9 PD-1 refractory & 9 PD-1 naïve). Objective response was observed in 3/9 PD-1 refractory, and in 5/9 PD-1 naïve patients, including two complete responses, one of which continues past 24 months. Responses were observed in HPV+ and HPV- patients and 5 responders had PD-L1 CPS scores of <5. We observed irAE's (G1-3, no G4), at a breadth & frequency greater than would be expected for PD-1 alone, attesting to bioactivity. Tumor biopsy analysis by scRNA-seq identified expanded T cell clones displaying tumor-reactive effector phenotypes which were not detectable at baseline (n=6 pts x 3 biopsy timepoints). In the first patient, TCR reconstruction and functional evaluation of three expanded T cell clones confirmed reactivity against HLA-matched tumors, with one TCR recognizing HNSCC, LUAD, RCC, and melanoma cell lines.
Conclusions
DPV-001 + sequenced d.PD-1 +/- GITR showed promising response rates of 56% (PD-1 naïve) and 33% (PD-1 refractory) in recurrent/metastatic HNSCC pts. Initial functional studies suggests this treatment expanded T cell clones against shared antigens. Ongoing studies are directed at unraveling the nature of the antigens recognized (canonical or dark matter), and whether they persist.
Acknowledgements
Incyte, Murdock Charitable Trust, Providence Portland Medical Foundation, Nancy Lematta, Lynn Loacker, Cindy and Steve Harder, The Chiles Foundation, Robert W. Franz and Elsie Franz Finley
Trial Registration
NCT04470024.
References
Nicoletta Cieri, Catherine J Wu. Splice it up: atypical transcripts to boost leukemia immunotherapy. Immunity 2021;54:608–610 Bernard A Fox, Walter J Urba, Shawn M Jensen, David B Page, Brendan D Curti, Rachel E Sanborn, Rom S Leidner. Cancer's Dark Matter: Lighting the Abyss Unveils Universe of New Therapies. Clin. Can. Res. Clin Cancer Res 2023;29(12):2173–2175.
Ethics Approval
This study was approved by Providence Health System's Ethics Board; approval number 2020000480.
As deforestation progresses in the tropics, wildlife populations are increasingly restricted to forest fragments. Here we study genetic population structure in the endangered Ashy red colobus (Piliocolobus tephrosceles) population in the forest fragments surrounding Kibale National Park, Uganda. Subsequently, we use landscape features (elevation, road data and distance to the park) to design a feasible strategy to restore forest in a fashion suitable for both the dispersal patterns of the species and land use practices of the local people. A lack of association between geographic distance and pairwise genetic relatedness among localities, the presence of first degree relatives across localities, and a low global Fst value suggest that red colobus individuals have migrated across this landscape in the recent past. Thus, a series of "stepping stone" forests from the fragments to the park will likely maintain viability of red colobus fragment populations. In this area, low-lying valleys are legally protected to prevent flooding and are considered of low-economic value to local people. We identify such valleys for development of community-based forest restoration efforts that will aid in red colobus conservation and provide various ecosystem services. Our study outlines how genetics and community-based restoration can be integrated to provide realistic conservation solutions.
Significance Social adversity is strongly linked to health and fitness outcomes in humans and other social mammals. This observation arises in part through “biological embedding”: persistent, social environment-induced biological changes that may affect immune function. Here we show that low social status in female rhesus macaques leads to a highly proinflammatory response to both bacterial and viral challenge. In addition, we show that past social status also affects gene expression, and that past low status leads to reduced sensitivity to current social conditions. Thus, the first line of defense in the macaque immune system is altered by both current social conditions and a biological memory of past events. Our results provide insight into how social adversity gets under the skin over long time spans.
ABSTRACT Variation in social status predicts molecular, physiological, and life history outcomes across a broad range of species, including our own. Experimental studies indicate that some of these relationships persist even when the physical environment is held constant. Here, we draw on data sets from one such study—experimental manipulation of dominance rank in captive female rhesus macaques—to investigate how social status shapes the lived experience of these animals to alter gene regulation, glucocorticoid physiology, and mitochondrial DNA phenotypes. We focus specifically on dominance rank-associated dimensions of the social environment, including both competitive and affiliative interactions. Our results show that simple summaries of rank-associated behavioral interactions are often better predictors of molecular and physiological outcomes than dominance rank itself. However, while measures of immune function are best explained by agonism rates, glucocorticoid-related phenotypes tend to be more closely linked to affiliative behavior. We conclude that dominance rank serves as a useful summary for investigating social environmental effects on downstream outcomes. Nevertheless, the behavioral interactions that define an individual’s daily experiences reveal the proximate drivers of social status-related differences, and are especially relevant for understanding why individuals who share the same social status sometimes appear physiologically distinct.
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