Biology subjects

Fuentes, C.

Publications and source records attributed to Fuentes, C..

4 recordsLinked to original sources

bioRxiv2022

Nuanced role for dendritic cell intrinsic IRE1 RNase in the regulation of antitumor adaptive immunity.

The IRE1/XBPls axis of the unfolded protein response (UPR) plays divergent roles in dendritic cell (DC) biology in steady state versus tumor contexts. Whereas tumor associated DCs show dysfunctional IRE1/XBP1s activation that curtails their function, the homeostasis of conventional type 1 DCs (cDC1) in tissues requires intact IRE1 RNase activity. Considering that cDC1s are key orchestrators of antitumor immunity, it is relevant to understand the functional versus dysfunctional roles of IRE1/XBP1s in tumor DC subtypes. Here, we show that cDC1s constitutively activate IRE1 RNase within subcutaneous B16 melanoma and MC38 adenocarcinoma tumor models. Mice lacking XBP1s in DCs display increased melanoma tumor growth, reduced T cell effector responses and accumulation of terminal exhausted CD8+ T cells. Transcriptomic studies revealed that XBP1 deficiency in tumor cDCls decreased expression of mRNAs encoding XBPls and regulated IRE1 dependent decay (RIDD) targets. Finally, we find that the dysregulated melanoma growth and impaired T cell immunity noticed in XBP1 deficient mice are attributed to RIDD induction in DCs. This work indicates that IREl RNase activity in melanoma/MC38-associated DCs fine tunes aspects of antitumor immunity independently of XBP1s, revealing a differential role for the UPR axis that depends on the DC subtype and cancer model.

immunology↗

bioRxiv2021

Offspring of first-generation hatchery steelhead trout (Oncorhynchus mykiss) grow faster in the hatchery than offspring of wild fish, but survive worse in the wild: possible mechanisms for inadvertent domestication and fitness loss in hatchery salmon

Salmonid fish raised in hatcheries often have lower fitness (number of returning adult offspring) than wild fish when both spawn in the wild. Body size at release from hatcheries is positively correlated with survival at sea. So one explanation for reduced fitness is that hatcheries inadvertently select for trait values that enhance growth rate under the unnatural environment of a hatchery, but that are maladaptive in the wild environment. A simple prediction of this hypothesis is that juveniles of hatchery origin should grow more quickly than fish of wild origin under hatchery conditions, but should have lower survival under wild conditions. We tested that hypothesis using multiple full sibling families of steelhead (Oncorhynchus mykiss) that were spawned using either two wild parents (WxW) or two first-generation hatchery (HxH) parents. Offspring from all the families were grown together under hatchery conditions and under semi-natural conditions in artificial streams. HxH families grew significantly faster in the hatchery, but had significantly lower survival in the streams. That we see this tradeoff after only a single generation of selection suggests that the traits involved are under very strong selection. We also considered one possible alteration to the hatchery environment that might reduce the intensity of selection among families in size at release. Here we tested whether reducing the fat content of hatchery feed would reduce the variance among families in body size. Although fish raised under a low-fat diet were slightly smaller, the variation among families in final size was unchanged. Thus, there is no evidence that reducing the fat content of hatchery feed would reduce the opportunity for selection among families on size at release.

zoology↗

bioRxiv2020

Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

Oral rapamycin administration rapamycin is plagued by poor bioavailability and wide biodistribution. Thus, this pleotropic mTOR inhibitor has a narrow therapeutic window, numerous side effects and provides inadequate transplantation protection. Parental formulation was not possible due to rapamycins hydrophobicity (log P 4.3). Here, we demonstrate that subcutaneous rapamycin delivery via poly(ethylene glycol)-b-poly(propylene sulfide)(PEG-b-PPS) polymersome (PS) nanocarriers modulates cellular biodistribution of rapamycin to change its immunosuppressive mechanism for enhanced efficacy while minimizing side effects. While oral rapamycin inhibits naive T cell proliferation directly, subcutaneously administered rapamycin-loaded polymersomes (rPS) instead modulated Ly-6Clow monocytes and tolerogenic semi-mature dendritic cells, with immunosuppression mediated by CD8+ Tregs and rare CD4+ CD8+ double-positive T cells. As PEG-b-PPS PS are uniquely non-inflammatory, background immunostimulation from the vehicle was avoided, allowing immunomodulation to be primarily attributed to rapamycins cellular biodistribution. Repurposing mTOR inhibition significantly improved maintenance of normoglycemia in a clinically relevant, MHC-mismatched, allogeneic, intraportal (liver) islet transplantation model. These results demonstrate the ability of engineered nanocarriers to repurpose drugs for alternate routes of administration by rationally controlling cellular biodistribution.

bioengineering↗

bioRxiv2020

Family variation in surface feeding behavior of steelhead fry predicts growth rate under hatchery conditions

Hatchery reared salmonid fish often have lower fitness than their natural-origin counterparts when spawning in the wild. Although this difference appears to result from rapid adaptation to captivity, it is not known what traits are under selection. We hypothesize that variation in traits that confer a growth rate advantage to some individuals in the novel hatchery environment are under strong selection because survival at sea is correlated with size at release. Here we show that full sibling families of steelhead trout (Oncorhynchus mykiss) show substantial variation in propensity to feed at the surface as fry, and that the more surface-oriented families grew faster under hatchery conditions. We hypothesize that surface-oriented fry gain an initial growth advantage that persists through size at release. Because surface orientation is a correlate of generalized boldness, hatcheries may inadvertently select for that phenotype, which could explain the fitness differences observed between hatchery and natural-origin fish in the wild.

zoology↗