Tumor Cell‐Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid β‐Oxidation

Li, Jiang; Xia, Qi‐Dong; Di, Can; Li, Chunni; Si, Hang; Zhou, Boxuan; Yu, Shubin; Li, Yihong; Huang, Jingying; Lu, Yiwen; Huang, Min; Liang, Huixin; Li, Xinwei; Zhao, Qiyi

doi:10.1002/advs.202202956

Cited by 14 publications

(12 citation statements)

References 73 publications

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“…In addition to immune cells, a recent study revealed CD96 expression in human breast cancer cells. High CD96 expression in the tissue samples was associated with poor prognosis [ 27 ]. The CD96 + breast cancer cells revealed cancer stem cell characteristics and showed increased resistance to chemotherapy [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…High CD96 expression in the tissue samples was associated with poor prognosis [ 27 ]. The CD96 + breast cancer cells revealed cancer stem cell characteristics and showed increased resistance to chemotherapy [ 27 ]. Blocking of CD96 in an immunocompromised xenotransplant mouse model of human breast cancer cells showed reduced tumor growth and increased apoptosis [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

“…The CD96 + breast cancer cells revealed cancer stem cell characteristics and showed increased resistance to chemotherapy [ 27 ]. Blocking of CD96 in an immunocompromised xenotransplant mouse model of human breast cancer cells showed reduced tumor growth and increased apoptosis [ 27 ]. This is interesting as immune cells play no role in this in vivo model.…”

Section: Discussionmentioning

confidence: 99%

“…This is interesting as immune cells play no role in this in vivo model. These data suggest that blocking CD96 may have direct anti-tumor effects independent of the immune system [ 27 ]. In the immunohistochemical analysis of the current study, there was a clear dominance of CD96 expression in tumor-infiltrating cells.…”

Section: Discussionmentioning

confidence: 99%

“…This indicates that the direct tumor cell-bound expression of CD96 might also be relevant in oral cancer. In the described mouse model, the expression of the CD96 ligand CD155 was also proven on breast cancer cells [ 27 ]. This indicates that CD96 signaling can be initiated by tumor cells and that CD155–CD96 interaction contributes to chemoresistance in breast cancer cells independent of immune cells [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

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The Immune Checkpoint Receptor CD96: A Local and Systemic Immune Modulator in Oral Cancer?

Trumet

Weber

Hahn

et al. 2023

Cancers

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Background: As immunotherapy of oral squamous cell carcinomas (OSCCs), using PD1 inhibitors, is only efficient in a small proportion of patients, additional immune checkpoints need to be identified as potential therapeutic targets. There is evidence that a blockade of CD96 might positively affect the anti-tumor immune response. The aim of this study was to analyze the gene and protein expression of CD96 in the tissue and peripheral blood of OSCC patients compared to healthy controls, while also checking for potential associations with a differential expression to the histomorphological parameters. In addition, possible correlations with the expression of PD1 and PD-L1 as well as the macrophage markers CD68 and CD163 should be tested to obtain further insights into the potential effectiveness of combined checkpoint blockage. Material and Methods: For real-time quantitative polymerase chain reaction (RT-qPCR), a total of 183 blood and tissue samples, divided into a patient and a control group, were included. Additionally, 141 tissue samples were examined by immunohistochemistry (IHC). The relative expression differences between the groups were calculated using statistical tests including the Mann–Whitney U test and AUC method. The Chi-square test was used to determine whether CD96 overexpression in individual samples is associated with malignancy. Correlation analysis was performed using the Spearman correlation test. Results: There was a significant CD96 mRNA and protein overexpression in the OSCC group compared to the controls (p = 0.001). In contrast, CD96 mRNA expression in the peripheral blood of the OSCC patients was significantly lower compared to the control group (p = 0.007). In the Chi-square test, the OSCC tissue samples showed a highly significant upregulation of CD96 mRNA expression (p < 0.001) and protein expression (p = 0.005) compared to the healthy mucosa. CD96 mRNA and protein expression correlated significantly (p = 0.005). In addition, there was a significant positive correlation of CD96 expression with PD1 (p ≤ 0.001), PD-L1 (p ≤ 0.001), and CD163 (p = 0.006) at the mRNA level. Conclusions: CD96 expression in the tumor tissue and peripheral blood of OSCC patients is differentially regulated and appears to be a relevant immune checkpoint.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

The Immune Checkpoint Receptor CD96: A Local and Systemic Immune Modulator in Oral Cancer?

Trumet

Weber

Hahn

et al. 2023

Cancers

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Tumor Cell‐Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid β‐Oxidation

Xia

et al. 2022

Advanced Science

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Targeting CD96 that originates in immune cells has shown potential for cancer therapy. However, the role of intrinsic CD96 in solid tumor cells remains unknown. Here, it is found that CD96 is frequently expressed in tumor cells from clinical breast cancer samples and is correlated with poor long‐term prognosis in these patients. The CD96+ cancer cell subpopulations exhibit features of both breast cancer stem cells and chemoresistance. In vivo inhibition of cancer cell‐intrinsic CD96 enhances the chemotherapeutic response in a patient‐derived tumor xenograft model. Mechanistically, CD96 enhances mitochondrial fatty acid β‐oxidation via the CD155‐CD96‐Src‐Stat3‐Opa1 pathway, which subsequently promotes chemoresistance in breast cancer stem cells. A previously unknown role is identified for tumor cell‐intrinsic CD96 and an attractive target in improving the chemotherapeutic response.

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Fatty Acid Oxidation Supports Lymph Node Metastasis of Cervical Cancer via Acetyl‐CoA‐Mediated Stemness

Yuan,

Jiang,

Jia

et al. 2024

Advanced Science

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Accumulating evidence indicates that metabolic reprogramming of cancer cells supports the energy and metabolic demands during tumor metastasis. However, the metabolic alterations underlying lymph node metastasis (LNM) of cervical cancer (CCa) have not been well recognized. In the present study, it is found that lymphatic metastatic CCa cells have reduced dependency on glucose and glycolysis but increased fatty acid oxidation (FAO). Inhibition of carnitine palmitoyl transferase 1A (CPT1A) significantly compromises palmitate‐induced cell stemness. Mechanistically, FAO‐derived acetyl‐CoA enhances H3K27 acetylation (H3K27Ac) modification level in the promoter of stemness genes, increasing stemness and nodal metastasis in the lipid‐rich nodal environment. Genetic and pharmacological loss of CPT1A function markedly suppresses the metastatic colonization of CCa cells in tumor‐draining lymph nodes. Together, these findings propose an effective method of cancer therapy by targeting FAO in patients with CCa and lymph node metastasis.

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Tumor Cell‐Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid β‐Oxidation

Cited by 14 publications

References 73 publications

The Immune Checkpoint Receptor CD96: A Local and Systemic Immune Modulator in Oral Cancer?

The Immune Checkpoint Receptor CD96: A Local and Systemic Immune Modulator in Oral Cancer?

Tumor Cell‐Intrinsic CD96 Mediates Chemoresistance and Cancer Stemness by Regulating Mitochondrial Fatty Acid β‐Oxidation

Fatty Acid Oxidation Supports Lymph Node Metastasis of Cervical Cancer via Acetyl‐CoA‐Mediated Stemness

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