Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers
Abstract
:Simple Summary
Abstract
1. Introduction
1.1. The Role of the Gut Microbiota in the Initiation and Progression of MSI CRC
1.2. CRC MMR Deficiency and Immune Surveillance
1.3. Mutational Characteristics of Mismatch-Repair-Deficient Cancer Cells
1.4. MMR Deficient Tumors Alert the Immune System, Triggering Cytotoxic T Cells and Inducing an INF-Mediated Immune Response
1.4.1. Neoantigen-Dependent Activation of Immune Surveillance in MMR-Deficient Colorectal Cancers
1.4.2. Cytosolic DNA Release Contributes to the Immunogenic Properties of MMRd Tumors
1.5. The Role of Checkpoint Inhibitor Treatment in MSI mCRC Patients
2. Non-Genetic Mechanisms of Immune Evasion in Microsatellite Unstable CRC
2.1. Altered Expression of Inhibitory Immune Checkpoints
2.2. Cytokines, Chemokines, and Factors Orchestrate an Immune Suppressive Microenvironment in MSI Cancer
2.3. cGas-STING Pathway May Alter the Immunogenicity of Cancer Cells and Favor an Immune Suppressive Microenvironment
2.4. Suppressive Immune Cell Compartments in MSI CRC
2.4.1. Regulatory T Cells
2.4.2. The Role of Myeloid-Derived Suppressor Cells
2.4.3. Tumor Associated Macrophages
3. Genetic Mechanisms of Immune Evasion in MSI CRC
3.1. Antigen Presenting Machinery Disruption in MSI Tumors
3.2. Deregulation of WNT Signalling Pathway Alters Tumor Microenvironment, Causing T-Cell Exclusion
3.3. Alterations in JAK-STAT Pathway Orchestrate Cancer Immune Evasion
3.4. Germline Genetic Variants Affect Different Immunomodulatory Pathways
3.5. The Intra-Tumoral Genetic Diversity of MMR Status as a Mechanism of Immune Escape
4. Translational Implications
5. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Lexical of Abbreviations
5-FU | 5-fluorouracil |
APC | Antigen presenting cell |
APM | Antigen presenting machinery |
B2M | β 2 microglobulin |
BMMR-D | Biallelic mismatch repair deficiency syndrome |
CCL | Chemokine (cc motif) ligand |
cGAMP | Cyclic guanosine monophosphate-adenosine monophosphate |
c-GAS | Cyclic GMP-AMP synthase |
CIMP | CpG island methylator phenotype |
CMS | Consensus molecular subtype |
CN-LOH | Copy-neutral loss of heterozygosity |
CPIs | Checkpoint inhibitors |
CRC | Colorectal cancer |
CSF1-R | Colony stimulating factor 1 receptor |
CTLA4 | Cytotoxic T-lymphocyte antigen 4 |
CTNNB1 | β -catenin |
CXC | Chemokine (cxc motif) |
CXCL | Chemokine (cxc motif) ligand |
DBS | Double base substitution |
DC | Dendritic cell |
DCR | Disease control rate |
DFCI | Dana Farber Cancer Institute |
DOR | Duration of response |
ENPP1 | Ectonucleotide pyrophosphatase/phosphodiesterase 1 |
ERP57 | Endoplasmic reticulum protein 57 |
EXO 1 | Exonuclease 1 |
FOXP 3 | Forkhead box 3 |
FS | Frameshift |
GATA3 | GATA binding protein 3 |
GROα | Growth regulated protein α |
GSK3B | Glycogen synthase kinase 3 beta |
HLA | Human leukocyte antigen |
HNPCC | Hereditary non-polyposis colorectal cancer |
HPV | Human Papilloma Virus |
ICOS | Inducible T-cell costimulator |
IDO | Indoleamine 2,3-dioxygenase |
IL- | Interleukin- |
IL1RA | IL-1 receptor agonist |
IN/DEL | Insertion/deletion |
INF | Interferon |
IRF3 | Interferon regulatory factor 3 |
JAK | Janus kinases |
LAG3 | Lymphocyte activation gene 3 |
M1 | M1-like macrophages |
M2 | M2-like macrophages |
mCRC | Metastatic CRC |
MDSC | Myeloid derived suppressor cells |
MGMT | O6-methylguanine-DNA methyltransferase |
MHC | Major histocompatibility complex |
MLH1 | MutL homolog 1 |
MMR | Mismatch repair |
MMRd | Mismatch repair deficient |
MMRp | Mismatch repair proficient |
mPFS | Median progression free survival |
MSH2 | MutS homolog 2 |
MSH6 | MutS homolog 6 |
MSI | Microsatellite instability |
MSS | Microsatellite stable |
NFKB | Nuclear factor Kappa-ligand-chain-enhancer of activated B cells |
NGS | Next generation sequencing |
NK | Natural killer |
NKG2D | Natural killer group 2 member D |
NLRC5 | NLR family CARD domain containing 5 |
NSCLC | Non-small cell lung cancer |
ORR | Objective response rate |
OS | Overall survival |
PD-1 | Programmed cell death protein 1 |
PD-L1 | Programmed cell death protein ligand 1 |
PFS | Progression free survival |
PMS2 | PMS1 homolog 2 |
POLD1 | Polymerase delta 1 |
POLE | Polymerase epsilon |
RAE1 | Retinoic acid early transcript 1 ligand |
RCC | Renal cell carcinoma |
RFX5 | Regulatory factor X5 |
ROS | Reactive oxygen species |
RPA | Replication protein A |
SBS | Single base substitution |
SNVs | Single nucleotide variants |
STAT | Signal transducer and activator of transcription |
STING | Stimulator of interferon gene |
TAM | Tumor associated macrophages |
TAP | Transporter associated with antigen processing |
TCF4 | T cell factor 4 |
TCGA | The Cancer Genome Atlas |
TCR | T cell receptor |
Tfh | T follicular helper |
TGFBR2 | TGF-β receptor 2 |
TGF-β | Transforming growth factor β |
Th1 | T-helper type 1 |
TIM3 | T-cell immunoglobulin and mucin domain-3 |
TMB | Tumor mutational burden |
Treg | Regulatory T cells |
VEGF | Vascular endothelial growth factor |
VISTA | V-domain Ig suppressor of T cell activation |
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Clinical Strategy | Trial Identifier | Phase | Regimen |
---|---|---|---|
CPIs combinations | NCT04008030 (CheckMate 8HW) | III | Nivolumab and ipilimumab vs. standard cytotoxic regimens |
CPIs plus targeted agents - RAS inhibitors - BRAF inhibitors | NCT03785249 (Krystal 1) | I/II | MRTX849 and pembrolizumab |
NCT04185883 (Codebreak) | Ib/II | Sotorasib + PD1i | |
NCT03668431 | II | Dabrafenib + trametinib + spartalizumab | |
NCT04294160 | Ib | Dabrafenib + LTT462 (ERKi) + Spartalizumab (PDR001) | |
CPIs plus cytotoxic and/or anti-VEGF agents | NCT02997228 (COMMIT) | III | FOLFOX + bevacizumab + atezolizumab vs. atezolizumab monotherapy vs. FOLFOX + bevacizumab |
CPIs plus radiotherapy | NCT04001101 | II | Pembrolizumab ± RT |
NCT03104439 | II | Nivolumab + ipilimumab + RT | |
Converting strategy | NCT03519412 (ARETHUSA) | II | Temozolomide followed by pembrolizumab |
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Amodio, V.; Mauri, G.; Reilly, N.M.; Sartore-Bianchi, A.; Siena, S.; Bardelli, A.; Germano, G. Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers. Cancers 2021, 13, 2638. https://doi.org/10.3390/cancers13112638
Amodio V, Mauri G, Reilly NM, Sartore-Bianchi A, Siena S, Bardelli A, Germano G. Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers. Cancers. 2021; 13(11):2638. https://doi.org/10.3390/cancers13112638
Chicago/Turabian StyleAmodio, Vito, Gianluca Mauri, Nicole M. Reilly, Andrea Sartore-Bianchi, Salvatore Siena, Alberto Bardelli, and Giovanni Germano. 2021. "Mechanisms of Immune Escape and Resistance to Checkpoint Inhibitor Therapies in Mismatch Repair Deficient Metastatic Colorectal Cancers" Cancers 13, no. 11: 2638. https://doi.org/10.3390/cancers13112638