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Tumor cell-intrinsic CD274/PD-L1: A novel metabolic balancing act with clinical potential
Curtis A Clark1, Harshita B Gupta2, Tyler J Curiel1,2,3
1a Graduate School of Biomedical Sciences , University of Texas Health Science Center , San Antonio , TX , USA.
Abstract:
Tumor expression of the immune co-signaling molecule CD274/PD-L1 was originally described as impeding antitumor immunity by direct engagement of its receptor, PDCD1/PD-1, on antitumor T cells. Melanoma-intrinsic PDCD1 was recently shown to promote tumor growth and MTOR signals in cooperation with tumor CD274, and sarcoma-intrinsic CD274 signaling promotes glucose metabolism to impede antitumor immunity. Our recent report shows that tumor cell-intrinsic CD274 promotes MTORC1 signaling in mouse melanoma and mouse and human ovarian cancer, inhibits autophagy and sensitizes some tumors to clinically available pharmacological autophagy inhibitors and confers resistance to MTOR inhibitors. Tumor CD274 could be a biomarker of autophagy or MTOR inhibitor response in selected tumors, and these inhibitors could improve anti-CD274 or anti-PDCD1 cancer immunotherapy. As we found that distinct tumor types exhibit this CD274-driven phenotype, it could be widely applicable.
Insights
Tumor CD274 (PD-L1) promotes cancer growth by inhibiting autophagy and sensitizing tumors to autophagy inhibitors. This finding may improve cancer immunotherapy by identifying biomarkers for treatment response.
Area of Science:
- Immunology
- Oncology
- Molecular Biology
Background:
- Tumor expression of CD274 (PD-L1) was initially understood to hinder antitumor immunity via PDCD1 (PD-1) receptor engagement on T cells.
- Recent studies indicate tumor-intrinsic PDCD1 promotes growth and MTOR signaling with CD274, while sarcoma CD274 signaling impacts glucose metabolism.
- CD274's role in cancer progression and immune evasion is complex and varies across tumor types.
Purpose of the Study:
- To investigate the role of tumor cell-intrinsic CD274 in regulating MTORC1 signaling and autophagy in cancer.
- To determine if CD274 influences sensitivity to autophagy and MTOR inhibitors.
- To explore the potential of CD274 as a biomarker for predicting response to these inhibitors and improving cancer immunotherapy.
Main Methods:
- Analysis of tumor cell-intrinsic CD274 expression and its impact on MTORC1 signaling pathways.
- Assessment of autophagy inhibition and sensitization to pharmacological inhibitors in mouse melanoma and human ovarian cancer models.
- Evaluation of tumor response to MTOR inhibitors in the context of CD274 expression.
Main Results:
- Tumor cell-intrinsic CD274 was found to promote MTORC1 signaling and inhibit autophagy in mouse melanoma and human ovarian cancer.
- This CD274-driven phenotype sensitizes tumors to clinically available autophagy inhibitors.
- Tumors with this phenotype exhibit resistance to MTOR inhibitors and CD274 may serve as a biomarker for treatment response.
Conclusions:
- Tumor-intrinsic CD274 plays a critical role in promoting cancer growth by modulating MTORC1 signaling and autophagy.
- CD274 expression can predict response to autophagy and MTOR inhibitors, suggesting potential therapeutic strategies.
- Targeting CD274 or utilizing autophagy/MTOR inhibitors may enhance the efficacy of anti-CD274/anti-PDCD1 cancer immunotherapies across various tumor types.