PMID- 30497521 OWN - NLM STAT- MEDLINE DCOM- 20190322 LR - 20240404 IS - 1756-994X (Electronic) IS - 1756-994X (Linking) VI - 10 IP - 1 DP - 2018 Nov 29 TI - Genomics of response to immune checkpoint therapies for cancer: implications for precision medicine. PG - 93 LID - 10.1186/s13073-018-0605-7 [doi] LID - 93 AB - Immune checkpoint blockade (ICB) therapies, which potentiate the body's natural immune response against tumor cells, have shown immense promise in the treatment of various cancers. Currently, tumor mutational burden (TMB) and programmed death ligand 1 (PD-L1) expression are the primary biomarkers evaluated for clinical management of cancer patients across histologies. However, the wide range of responses has demonstrated that the specific molecular and genetic characteristics of each patient's tumor and immune system must be considered to maximize treatment efficacy. Here, we review the various biological pathways and emerging biomarkers implicated in response to PD-(L)1 and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) therapies, including oncogenic signaling pathways, human leukocyte antigen (HLA) variability, mutation and neoantigen burden, microbiome composition, endogenous retroviruses (ERV), and deficiencies in chromatin remodeling and DNA damage repair (DDR) machinery. We also discuss several mechanisms that have been observed to confer resistance to ICB, such as loss of phosphatase and tensin homolog (PTEN), loss of major histocompatibility complex (MHC) I/II expression, and activation of the indoleamine 2,3-dioxygenase 1 (IDO1) and transforming growth factor beta (TGFbeta) pathways. Clinical trials testing the combination of PD-(L)1 or CTLA-4 blockade with molecular mediators of these pathways are becoming more common and may hold promise for improving treatment efficacy and response. Ultimately, some of the genes and molecular mechanisms highlighted in this review may serve as novel biological targets or therapeutic vulnerabilities to improve clinical outcomes in patients. FAU - Conway, Jake R AU - Conway JR AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. AD - Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, 02142, USA. AD - Department of Biomedical Informatics, Harvard Medical School, Boston, MA, 02215, USA. FAU - Kofman, Eric AU - Kofman E AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. AD - Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, 02142, USA. FAU - Mo, Shirley S AU - Mo SS AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. AD - Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, 02142, USA. FAU - Elmarakeby, Haitham AU - Elmarakeby H AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. AD - Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, 02142, USA. AD - Department of System and Computer Engineering, Al-Azhar University, Cairo, 11751, Egypt. FAU - Van Allen, Eliezer AU - Van Allen E AD - Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. eliezerm_vanallen@dfci.harvard.edu. AD - Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA, 02142, USA. eliezerm_vanallen@dfci.harvard.edu. LA - eng GR - R01 CA227388/CA/NCI NIH HHS/United States GR - T32 HG002295/HG/NHGRI NIH HHS/United States GR - 5T32HG002295-15/NH/NIH HHS/United States GR - R01CA227388/NH/NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Review DEP - 20181129 PL - England TA - Genome Med JT - Genome medicine JID - 101475844 RN - 0 (B7-H1 Antigen) RN - 0 (CD274 protein, human) RN - 0 (CTLA-4 Antigen) RN - 0 (CTLA4 protein, human) SB - IM MH - Animals MH - B7-H1 Antigen MH - CTLA-4 Antigen MH - Drug Resistance, Neoplasm MH - Genomics MH - Humans MH - *Immunotherapy MH - Neoplasms/*genetics/immunology/therapy MH - Precision Medicine MH - Signal Transduction PMC - PMC6264032 OTO - NOTNLM OT - Biomarkers OT - CTLA-4 OT - Cancer OT - Checkpoint OT - Genomic OT - Immunotherapy OT - Inhibitor OT - PD-1 OT - Response COIS- COMPETING INTERESTS: The authors declare that they have no competing interests. PUBLISHER'S NOTE: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. EDAT- 2018/12/01 06:00 MHDA- 2019/03/23 06:00 PMCR- 2018/11/29 CRDT- 2018/12/01 06:00 PHST- 2018/12/01 06:00 [entrez] PHST- 2018/12/01 06:00 [pubmed] PHST- 2019/03/23 06:00 [medline] PHST- 2018/11/29 00:00 [pmc-release] AID - 10.1186/s13073-018-0605-7 [pii] AID - 605 [pii] AID - 10.1186/s13073-018-0605-7 [doi] PST - epublish SO - Genome Med. 2018 Nov 29;10(1):93. doi: 10.1186/s13073-018-0605-7.