ABSTRACT
Colorectal cancer (CRC) is one of the most common malignancies in both morbidity and mortality. Immune checkpoint blockade (ICB) treatments have been successful in a portion of mismatch repair-deficient (dMMR) CRC patients but have failed in mismatch repair-proficient (pMMR) CRC patients. Atypical Chemokine Receptor 4 (ACKR4) is implicated in regulating dendritic cell (DC) migration. However, the roles of ACKR4 in CRC development and anti-tumor immunoregulation are not known. By analyzing human CRC tissues, transgenic animals, and genetically modified CRC cells lines, our study revealed an important function of ACKR4 in maintaining CRC immune response. Loss of ACKR4 in CRC is associated with poor immune infiltration in the tumor microenvironment. More importantly, loss of ACKR4 in CRC tumor cells, rather than stromal cells, restrains the DC migration and antigen presentation to the tumor-draining lymph nodes (TdLNs). Moreover, tumors with ACKR4 knockdown become less sensitive to immune checkpoint blockade. Finally, we identified that microRNA miR-552 negatively regulates ACKR4 expression in human CRC. Taken together, our studies identified a novel and crucial mechanism for the maintenance of the DC-mediated T-cell priming in the TdLNs. These new findings demonstrate a novel mechanism leading to immunosuppression and ICB treatment resistance in CRC.
ABSTRACT
BACKGROUND: Attenuation of the peak impact force is essential in any protective devices for prevention of fall-related injuries. HYPOTHESIS: Common wrist guards have limited effectiveness because of the multifaceted nature of wrist injury mechanisms, and other modalities may provide enhanced shock-absorbing functions. STUDY DESIGN: Controlled laboratory study. METHODS: A free-fall device was constructed using a mechanical surrogate to simulate falling impact. At 4 different falling heights, 5 different hand conditions were tested: bare hand, a generic-brand wrist guard, a Sorbothane glove, an air cell, and an air bladder condition. The impact force from the ground and the transmitted impact force to the forearm/hand complex were simultaneously measured. RESULTS: The falling height and hand condition significantly modulated the impact responses. The padded conditions always had significantly smaller peak impact forces compared with the bare-hand condition. The wrist guard became ineffective in impact force attenuation beyond the falling height of 51 cm. On the other hand, the air bladder condition maintained less than 45% of the peak impact force of the bare-hand condition and remained below the critical value, whereas other conditions were all ineffective. CONCLUSION: It was reconfirmed that common wrist guard design could provide limited impact force attenuation, whereas damped pneumatic springs would provide substantially enhanced shock-absorbing functions. CLINICAL RELEVANCE: A wrist guard incorporating volar padding with the pneumatic spring design principle might be more effective at preventing injuries than are currently available designs.
