Hypoxia-inducing cryogels uncover key cancer-immune cell interactions in an oxygen-deficient tumor microenvironment  

作　　者：Thibault Colombani Zachary JRogers Khushbu Bhatt James Sinoimeri Lauren Gerbereux Mohammad Hamrangsekachaee Sidi ABencherif 

机构地区：[1]Department of Chemical Engineering,Northeastern University,Boston,MA 02115,United States [2]Department of Pharmaceutical Sciences,Northeastern University,Boston,MA,United States [3]Department of Bioengineering,Northeastern University,Boston,MA 02115,United States [4]Harvard John A.Paulson School of Engineering and Applied Sciences,Harvard University,Cambridge,MA 02138,United States [5]Biomechanics and Bioengineering(BMBI),UTC CNRS UMR 7338,University of Technology of Compi`egne,Sorbonne University,60203 Compi`egne,France

出　　处：《Bioactive Materials》2023年第11期279-295,共17页生物活性材料（英文）

基　　金：the National Institutes of Health(NIH,1R01EB027705 award);National Science Foundation(NSF CAREER award,DMR 1847843).

摘　　要：Hypoxia is a major factor shaping the immune landscape,and several cancer models have been developed to emulate hypoxic tumors.However,to date,they still have several limitations,such as the lack of reproducibility,inadequate biophysical cues,limited immune cell infiltration,and poor oxygen(O_(2))control,leading to non-pathophysiological tumor responses.Therefore,it is essential to develop better cancer models that mimic key features of the tumor extracellular matrix and recreate tumor-associated hypoxia while allowing cell infiltration and cancer-immune cell interactions.Herein,hypoxia-inducing cryogels(HICs)have been engineered using hyaluronic acid(HA)to fabricate three-dimensional microtissues and model a hypoxic tumor microenvironment.Specifically,tumor cell-laden HICs have been designed to deplete O_(2) locally and induce long-standing hypoxia.HICs promoted changes in hypoxia-responsive gene expression and phenotype,a metabolic adaptation to anaerobic glycolysis,and chemotherapy resistance.Additionally,HIC-supported tumor models induced dendritic cell(DC)inhibition,revealing a phenotypic change in the plasmacytoid DC(pDC)subset and an impaired conventional DC(cDC)response in hypoxia.Lastly,our HIC-based melanoma model induced CD8^(+)T cell inhibition,a condition associated with the downregulation of pro-inflammatory cytokine secretion,increased expression of immunomodulatory factors,and decreased degranulation and cytotoxic capacity of T cells.Overall,these data suggest that HICs can be used as a tool to model solid-like tumor microenvironments and has great potential to deepen our understanding of cancer-immune cell relationship in low O_(2) conditions and may pave the way for developing more effective therapies.

关 键 词：Cryogels Hypoxia CANCER IMMUNOSUPPRESSION Drug resistance 

分 类 号：R73[医药卫生—肿瘤]