Cancer Cell-Intrinsic Alterations Associated with an Immunosuppressive Tumor Microenvironment and Resistance to Immunotherapy in Lung Cancer
Abstract
:Simple Summary
Abstract
1. Introduction
2. Main Gene Mutations That Shape the Tumor Microenvironment in NSCLC
2.1. KRAS Mutations
2.2. STK11 Mutations
2.3. TP53 Mutations
2.4. EGFR Mutations
2.5. KEAP1 Mutations
2.6. Mutations in Genes of the Antigen Processing and Presentation Machinery
2.7. Mutations in other Genes with Potential Importance in Immunosuppression
3. Metabolic Rewiring in NSCLC and its Influence on the TME
3.1. Lactate
3.2. Hypoxia
3.3. Amino Acids
3.4. Lipids
3.5. Metabolic Rewiring by STK11 Alterations
3.6. Metabolic Rewiring by KEAP1 Alterations
4. Emerging Altered Cancer Pathways Associated with Immunosuppression in NSCLC
4.1. Wnt/β-Catenin
4.2. YES1
4.3. DSTYK
4.4. MUC1 and Hippo Pathways
4.5. DNA Damage Repair (DDR)
5. Cancer Cell-Intrinsic Genetic Alterations That Contribute to Immunosuppression in SCLC
5.1. Main Genetic Alterations Driving Immunosuppression in SCLC
5.2. Molecular Subtypes
5.3. Notch Signaling
5.4. Targeting DNA Damage Repair (DDR) in SCLC to Reshape the TME
5.5. Other Targets to Reshape the SCLC TME
6. Epigenetic Changes That Modify the TME in Lung Cancer and Immunotherapy Response
6.1. Epigenetic Alterations in NSCLC and SCLC
6.2. Epigenetic Changes in Lung Cancer Related to the Immune TME
7. Personalized Immunotherapy beyond ICIs
8. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Subtype | Clinical Trial Identifier | Phase and Status | Epigenetic Agent | Target | Combined Agent |
---|---|---|---|---|---|
NSCLC | NCT01928576 | Phase II; Ongoing | Azacitidine Entinostat | DNMT1 HDAC | Nivolumab |
NSCLC | NCT03233724 | Phase I/II; Completed | Decitabine Tetrahydrouridine | DNMT1 CDA | Pembrolizumab |
NSCLC | NCT03220477 | Phase I; Ongoing | Guadecitabine Mocetinostat | DNMT1 | Pembrolizumab |
NSCLC | NCT01209520 | Pilot study; Completed | Azacitidine | DNMT1 | Cisplatin Carboplatin Paclitaxel Vinorelbine Docetaxel Pemetrexed |
SCLC NSCLC | NCT02489903 | Phase II; Completed | RRx-001 | CD47 and SIRP-α | Cisplatin Etoposide Carboplatin Irinotecan Vinorelbine Doxil Gemcitabine Taxane Paclitaxel Nab-paclitaxel Pemetrexed |
NSCLC | NCT02959437 | Phase I/II; Terminated | Azacitidine INCB057643 INCB059872 | DNMT1 BET LSD1 | Pembrolizumab Epacadostat |
NSCLC | NCT02664181 | Phase II; Ongoing | Oral decitabine Tetrahdrouridine | DNMT1 CDA | Nivolumab |
NSCLC | NCT02638090 | Phase I/II; Ongoing | Vorinostat | HDAC | Pembrolizumab |
NSCLC | NCT02437136 | Phase IB/II; Ongoing | Entinostat | HDAC | Pembrolizumab |
SCLC | NCT02446704 | Phase I/II; Ongoing | Temozolomide | m5C | Olaparib |
SCLC | NCT01638546 | Phase II; Completed | Temozolomide | m5C | Veliparib |
NSCLC | NCT00423150 | Phase II; Terminated | Temozolomide | m5C | - |
SCLC | NCT01222936 | Phase II; Completed | LBH589 Panobinostat | HDAC | - |
SCLC | NCT02034123 | Phase I; Terminated | GSK2879552 | LSD1/KMD1A | - |
Metastatic solid tumor | NCT05268666 | Phase I/II; Ongoing | JBI-802 | LSD1/HDAC6 | - |
SCLC NSCLC | NCT04350463 | Phase II; Ongoing | CC-90011 | LSD1 | Nivolumab |
NSCLC | NCT05467748 | Phase I/II; Ongoing | Tazemetostat | EZH2 | Pembrolizumab |
SCLC | NCT03460977 | Phase I; Ongoing | PF-06821497 | EZH2 | - |
Lung neoplasms | NCT00978250 | Phase II; Completed | FdCyd Tetrahydrouridine | DNMT CDA | - |
NSCLC | NCT02546986 | Phase II; Ongoing | CC-486 | DNMT1 | Pembrolizumab |
NSCLC | NCT01478685 | Phase I; Completed | CC-486 | DNMT1 | Carboplatin Nab-paclitaxel |
NSCLC | NCT02250326 | Phase II; Ongoing | CC-486 | DNMT1 | Durvalumab Nab-paclitaxel |
NSCLC | NCT05573035 | Phase I; Ongoing | LYL845 | TILs | - |
NSCLC | NCT05607108 | Phase II; Ongoing | ZEN003694 | BET | - |
NSCLC | NCT01207726 | Phase II; Terminated | Azacitidine Entinostat | DNMT1 HDAC | - |
SCLC | NCT05191797 | Phase I/II; Ongoing | Bomedemstat | LSD1 | Atezolizumab |
NSCLC | NCT02635061 | Phase IB; Ongoing | ACY-241 | HDAC6 | Nivolumab |
NSCLC | NCT01059552 | Phase I; Completed | Vorinostat | HDAC | Cisplatin Pemetrexed Radiation 70Gy |
NSCLC | NCT00821951 | Phase I; Completed | Vorinostat | HDAC | Radiotherapy |
NSCLC | NCT02728492 | Phase I; Completed | Quisinostat | HDAC1 | Paclitaxel Carboplatin Gemcitabine Cisplatin |
NSCLC | NCT00667082 | Phase I; Completed | Vorinostat | HDAC | NPI-0052 Marizomib |
NSCLC | NCT00005093 | Phase III; Completed | Tacedinaline | HDAC | Gemcitabine |
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Otegui, N.; Houry, M.; Arozarena, I.; Serrano, D.; Redin, E.; Exposito, F.; Leon, S.; Valencia, K.; Montuenga, L.; Calvo, A. Cancer Cell-Intrinsic Alterations Associated with an Immunosuppressive Tumor Microenvironment and Resistance to Immunotherapy in Lung Cancer. Cancers 2023, 15, 3076. https://doi.org/10.3390/cancers15123076
Otegui N, Houry M, Arozarena I, Serrano D, Redin E, Exposito F, Leon S, Valencia K, Montuenga L, Calvo A. Cancer Cell-Intrinsic Alterations Associated with an Immunosuppressive Tumor Microenvironment and Resistance to Immunotherapy in Lung Cancer. Cancers. 2023; 15(12):3076. https://doi.org/10.3390/cancers15123076
Chicago/Turabian StyleOtegui, Nerea, Maeva Houry, Imanol Arozarena, Diego Serrano, Esther Redin, Francisco Exposito, Sergio Leon, Karmele Valencia, Luis Montuenga, and Alfonso Calvo. 2023. "Cancer Cell-Intrinsic Alterations Associated with an Immunosuppressive Tumor Microenvironment and Resistance to Immunotherapy in Lung Cancer" Cancers 15, no. 12: 3076. https://doi.org/10.3390/cancers15123076