Tackling Immunotherapy Resistance: Developing Rational Combinations of Immunotherapy and Targeted Drugs
Mechanisms of resistance to immunotherapies are multiple and complex with components intrinsic to the tumor cell and within the immune microenvironment. We review evidence of the interaction of tumor cell signaling pathways with immune pathways and the role this plays in de novo and acquired resista...
| Main Authors: | , , |
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| Format: | Article |
| Language: | English |
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Innovative Healthcare Institute
2019-05-01
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| Series: | Journal of Immunotherapy and Precision Oncology |
| Subjects: | |
| Online Access: | https://jipo.org/doi/pdf/10.4103/JIPO.JIPO_24_18 |
| _version_ | 1797962716291268608 |
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| author | Elena Cojocaru Mariana Scaranti Anna Minchom |
| author_facet | Elena Cojocaru Mariana Scaranti Anna Minchom |
| author_sort | Elena Cojocaru |
| collection | DOAJ |
| description | Mechanisms of resistance to immunotherapies are multiple and complex with components intrinsic to the tumor cell and within the immune microenvironment. We review evidence of the interaction of tumor cell signaling pathways with immune pathways and the role this plays in de novo and acquired resistance. The mitogen-activated protein kinase (MAPK) pathway activation and effects on T-cell function are discussed. Phosphoinositide 3-kinase (PI3K) pathway activation (including PTEN loss of function) correlates with T-cell inhibition and immunotherapy resistance. Wnt signaling has been implicated in T-cell function suppression. Key evidence from preclinical models exists for the role of these signaling pathways and is described. Clinical evidence is less advanced though correlation of mutations in key nodes with immune resistance provides a limited clinical correlation. Serial biomarker analysis in patients receiving targeted drugs has been attempted with notable examples including BRAF inhibition in melanoma patients resulting in dynamic changes in programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes. Drug combinations aim to overcome mechanisms of resistance, and recent years have seen numerous combinations of targeted therapies and immune checkpoint inhibitors proposed. However, clear biological rationale and thoughtful trial designs with a translational focus are required to allow such combinations to achieve their full potential. |
| first_indexed | 2024-04-11T01:17:14Z |
| format | Article |
| id | doaj.art-4c2bc6fe79694adfae16c628a5b61490 |
| institution | Directory Open Access Journal |
| issn | 2666-2345 2590-017X |
| language | English |
| last_indexed | 2024-04-11T01:17:14Z |
| publishDate | 2019-05-01 |
| publisher | Innovative Healthcare Institute |
| record_format | Article |
| series | Journal of Immunotherapy and Precision Oncology |
| spelling | doaj.art-4c2bc6fe79694adfae16c628a5b614902023-01-03T20:03:05ZengInnovative Healthcare InstituteJournal of Immunotherapy and Precision Oncology2666-23452590-017X2019-05-01233510.4103/JIPO.JIPO_24_18i2590-017X-2-2-23Tackling Immunotherapy Resistance: Developing Rational Combinations of Immunotherapy and Targeted DrugsElena CojocaruMariana ScarantiAnna MinchomMechanisms of resistance to immunotherapies are multiple and complex with components intrinsic to the tumor cell and within the immune microenvironment. We review evidence of the interaction of tumor cell signaling pathways with immune pathways and the role this plays in de novo and acquired resistance. The mitogen-activated protein kinase (MAPK) pathway activation and effects on T-cell function are discussed. Phosphoinositide 3-kinase (PI3K) pathway activation (including PTEN loss of function) correlates with T-cell inhibition and immunotherapy resistance. Wnt signaling has been implicated in T-cell function suppression. Key evidence from preclinical models exists for the role of these signaling pathways and is described. Clinical evidence is less advanced though correlation of mutations in key nodes with immune resistance provides a limited clinical correlation. Serial biomarker analysis in patients receiving targeted drugs has been attempted with notable examples including BRAF inhibition in melanoma patients resulting in dynamic changes in programmed death-ligand 1 (PD-L1) expression and tumor-infiltrating lymphocytes. Drug combinations aim to overcome mechanisms of resistance, and recent years have seen numerous combinations of targeted therapies and immune checkpoint inhibitors proposed. However, clear biological rationale and thoughtful trial designs with a translational focus are required to allow such combinations to achieve their full potential.https://jipo.org/doi/pdf/10.4103/JIPO.JIPO_24_18cellular pathwayscombinationearly-phase trialsimmunotherapy, resistance |
| spellingShingle | Elena Cojocaru Mariana Scaranti Anna Minchom Tackling Immunotherapy Resistance: Developing Rational Combinations of Immunotherapy and Targeted Drugs Journal of Immunotherapy and Precision Oncology cellular pathways combination early-phase trials immunotherapy, resistance |
| title | Tackling Immunotherapy Resistance: Developing Rational Combinations of Immunotherapy and Targeted Drugs |
| title_full | Tackling Immunotherapy Resistance: Developing Rational Combinations of Immunotherapy and Targeted Drugs |
| title_fullStr | Tackling Immunotherapy Resistance: Developing Rational Combinations of Immunotherapy and Targeted Drugs |
| title_full_unstemmed | Tackling Immunotherapy Resistance: Developing Rational Combinations of Immunotherapy and Targeted Drugs |
| title_short | Tackling Immunotherapy Resistance: Developing Rational Combinations of Immunotherapy and Targeted Drugs |
| title_sort | tackling immunotherapy resistance developing rational combinations of immunotherapy and targeted drugs |
| topic | cellular pathways combination early-phase trials immunotherapy, resistance |
| url | https://jipo.org/doi/pdf/10.4103/JIPO.JIPO_24_18 |
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