TY - JOUR
T1 - B7-H3 associates with IMPDH2 and regulates cancer cell survival
AU - Alhamad, Salwa
AU - Elmasry, Yassmin
AU - Uwagboe, Isabel
AU - Chekmeneva , Elena
AU - Sands, Caroline
AU - Cooper , Benjamin W.
AU - Camuzeaux, Stephane
AU - Salam, Ash
AU - Parsons, Maddy
N1 - Funding Information:
The authors would like to thank Brooke Lumicisi for assistance with molecular biology reagent generation, Alison John and Gisli Jenkins (Imperial College London) for assistance with human lung tissue, and Adrien Le Guennec for his help with running the speed-vacuum centrifuge. The National Phenome Centre was supported by the Medical Research Council and National Institute for Health Research (grant number MC_PC_12025), and infrastructure support was provided by the National Institute for Health Research (NIHR) and Imperial Biomedical Research Centre (BRC).
Funding Information:
This research was funded by Imam Abdulrahman Bin Faisal University, Saudi Arabia, and the Medical Research Council and National Institute for Health Research (grant number MC_PC_12025), Medical Research Council UK (MR/W031469/1), and Darwin Trust of Edinburgh. Infrastructure support was provided by the National Institute for Health Research (NIHR) and Imperial Biomedical Research Centre (BRC).
Publisher Copyright:
© 2023 by the authors.
PY - 2023/7/7
Y1 - 2023/7/7
N2 - Lung cancer is one of the most common cancers worldwide, and despite improvements in treatment regimens, patient prognosis remains poor. Lung adenocarcinomas develop from the lung epithelia and understanding how specific genetic and environmental factors lead to oncogenic transformation in these cells is of great importance to define the pathways that contribute to tumorigenesis. The recent rise in the use of immunotherapy to treat different cancers has prompted the exploration of immune modulators in tumour cells that may provide new targets to manipulate this process. Of these, the B7 family of cell surface receptors, which includes PD-1, is of particular interest due to its role in modulating immune cell responses within the tumour microenvironment. B7-H3 (CD276) is one family member that is upregulated in many cancer types and suggested to contribute to tumour–immune interactions. However, the function and ligand(s) for this receptor in normal lung epithelia and the mechanisms through which the overexpression of B7-H3 regulate cancer progression in the absence of immune cell interactions remain unclear. Here, we present evidence that B7-H3 is associated with one of the key rate-limiting metabolic enzymes IMPDH2, and the localisation of this complex is altered in human lung cancer cells that express high levels of B7-H3. Mechanistically, the IMPDH2:B7-H3 complex provides a protective role in cancer cells to escape oxidative stress triggered by chemotherapy, thus leading to cell survival. We further demonstrate that the loss of B7-H3 in cancer cells has no effect on growth or migration in 2D but promotes the expansion of 3D spheroids in an IMPDH2-dependent manner. These findings provide new insights into the B7-H3 function in the metabolic homeostasis of normal and transformed lung cancer cells, and whilst this molecule remains an interesting target for immunotherapy, these findings caution against the use of anti-B7-H3 therapies in certain clinical settings.
AB - Lung cancer is one of the most common cancers worldwide, and despite improvements in treatment regimens, patient prognosis remains poor. Lung adenocarcinomas develop from the lung epithelia and understanding how specific genetic and environmental factors lead to oncogenic transformation in these cells is of great importance to define the pathways that contribute to tumorigenesis. The recent rise in the use of immunotherapy to treat different cancers has prompted the exploration of immune modulators in tumour cells that may provide new targets to manipulate this process. Of these, the B7 family of cell surface receptors, which includes PD-1, is of particular interest due to its role in modulating immune cell responses within the tumour microenvironment. B7-H3 (CD276) is one family member that is upregulated in many cancer types and suggested to contribute to tumour–immune interactions. However, the function and ligand(s) for this receptor in normal lung epithelia and the mechanisms through which the overexpression of B7-H3 regulate cancer progression in the absence of immune cell interactions remain unclear. Here, we present evidence that B7-H3 is associated with one of the key rate-limiting metabolic enzymes IMPDH2, and the localisation of this complex is altered in human lung cancer cells that express high levels of B7-H3. Mechanistically, the IMPDH2:B7-H3 complex provides a protective role in cancer cells to escape oxidative stress triggered by chemotherapy, thus leading to cell survival. We further demonstrate that the loss of B7-H3 in cancer cells has no effect on growth or migration in 2D but promotes the expansion of 3D spheroids in an IMPDH2-dependent manner. These findings provide new insights into the B7-H3 function in the metabolic homeostasis of normal and transformed lung cancer cells, and whilst this molecule remains an interesting target for immunotherapy, these findings caution against the use of anti-B7-H3 therapies in certain clinical settings.
UR - http://www.scopus.com/inward/record.url?scp=85164919574&partnerID=8YFLogxK
U2 - 10.3390/cancers15133530
DO - 10.3390/cancers15133530
M3 - Article
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
IS - 13
M1 - 3530
ER -
