T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment
Abstract
:1. Introduction
1.1. Immune Cell Infiltration into the Consensus Molecular CRC Subtypes
- (I)
- Consensus Molecular Subtype (CMS) 1 is characterized by MSI and a hypermutated profile of mismatch repair genes and BRAF genes. Most CRCs with microsatellite instability are in the CMS1 subtype [9]. Due to microsatellite instability, CMS1 tumors have a high amount of neo-antigens that are not expressed in healthy tissues. CMS1 patients have an immune infiltrate consisting of T helper 1 (Th1) cells, natural killer (NK) cells, CD8+ cytotoxic T lymphocytes (CTL) and dendritic cells (DCs). About 14% of CRCs belong to the CMS1 subtype.
- (II)
- The CMS2 subtype includes CRCs with higher chromosomal instability (CIN) and microsatellite-stable tumors. CMS2 tumors lack DCs in the tumor microenvironment, indicating that the CMS2 subtype is only poorly immunogenic, with few tumor-infiltrating immune cells. CMS2 patients are characterized by the infiltration of a few naïve CD4+ T cells and resting NK cells. The WNT signaling pathway correlates with T cell exclusion in CRCs [10]. Approximately 37% of CRCs belong to CMS2.
- (III)
- The CMS3 subtype is the metabolic subtype, characterized by chromosomal instability and a higher level of KRAS mutations compared with other CMS phenotypes. Like CMS2, CMS3 shows only poor immune infiltration and no immune regulatory cytokines. Tumor-infiltrating lymphocytes (TILs) consist of naïve T cells and T helper 17 (Th17) cells. About 13% belong to the CMS3 subtype.
- (IV)
- The CMS4 subtype shows a high expression of genes specific for immunosuppressive TGF-β signaling and of genes specific to regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) [11]. CMS4 is also characterized by an upregulated expression of genes that encode chemokines that attract myeloid cells and T cells that produce interleukin 17 (IL-17), which are known to enhance carcinogenesis [12]. The CMS4 phenotype shows high levels of infiltrating macrophages and stromal cells. Approximately 23% of CRC tumors fall into CMS4. Although CMS4 patients show high levels of leukocyte infiltration, patients with CMS4 tumors have the worst prognosis of the four subtypes.
1.2. Differences between Cold, Altered-Excluded, Altered-Immunosuppressed and Hot CRCs
- (1)
- The optimal immunity with a high immunoscore and hot, “T cell inflamed” tumors.
- (2)
- The altered immunity with an intermediate immunoscore and an immunosuppressed phenotype.
- (3)
- The exclusion phenotype with an intermediate immunoscore and a high density of T cells only at the margin of the tumor.
- (4)
- The phenotype with a low immunoscore and cold, “non-T cell inflamed” tumors in which other immune cells, such as myeloid cells, can be observed.
1.3. T Cell Subsets in CRC
1.3.1. Conventional αβ CD4-Positive T Cells
1.3.2. Conventional αβ CD8-Positive T Cells
1.3.3. γδ T Cells
1.3.4. NKT Cells
Name | Surface Marker | Polarizing Cytokines | Function | Secreted Cytokines | Reference |
---|---|---|---|---|---|
CTL | CD8+ CCR4+ CXCR3+ IFNγR+ αβ TCR | IL-2, IL-7, IL-4, IL-15 | Destruction of tumor cells by cytotoxic molecules, e.g., perforin, granzymes, granulysin and Fas ligand. | IFN-γ, TNF-α, IL-2 | [142,143] |
iNKT | CXCR3+, NK1.1+ Vα24-Jα18 TCR | IL-12, IL-18 | Anti-tumoral functions mainly mediated by IFN-γ, TNF-α and downstream activation of NK cells and CTLs. Destruction of tumor cells by cytotoxic molecules. | IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-3, IL-13, IL-10, IL-17, IL-21, IL-22 | [132,136] |
Type II NKT | αβ TCR | Pro-tumoral functions mediated by IL-4 and IL-13. | IL-4, IL-13 | [132,136] | |
γδ T1 | γδ TCR CD27+ CD122+ CD45RB+ Fas-L+ | IL-2, IL-15 | Anti-tumoral functions mainly mediated by IFN-γ, TNF-α and downstream activation of NK cells and CTLs. Destruction of tumor cells by cytotoxic molecules. | IFN-γ, TNF-α, IL-2 | [119,144] |
γδ T17 | γδ TCR CCR6+ SCART-2+ | IL-23, IL-1β, IL-6, TGF-β | Regulator of epithelial barrier integrity. | IL-17 | [145,146] |
γδ T2 | γδ TCR | IL-4 | Maintain tolerance to self-antigens, prevent the induction of auto-antibodies. Suppression of effector T cell-mediated immune responses in colorectal cancer. | IL-4, TGF-β | [147] |
2. Tumor Initiation: Recognition of Colon Cancer Cells by T Cells
3. Tumor Progression: When Cancer Cells Escape T Cell Recognition
3.1. T Cell Exclusion
3.2. Dysfunctional T Cells
3.3. Tolerance, Anergy and Ignorance
3.4. Exhaustion
4. Immunotherapeutic Interventions
4.1. Immunotherapies with Immune Checkpoint Inhibitors
- (i)
- Ipilimumab, an antibody that binds CTLA-4, for melanoma treatment [191].
- (ii)
- Nivolumab, an antibody that binds PD-1, for melanoma treatment [192].
- (iii)
- Avelumab, an antibody against PD-L1 targeting the PD-L1/PD-1 pathway, for metastatic Merkel cell carcinoma [193].
- (iv)
- Atezolizumab, an engineered humanized immunoglobulin G1 antibody against PD-L1, for metastatic urothelial carcinoma [194].
- (v)
- Urelumab, an anti-CD137 antibody [195], for the treatment of different solid cancers, such as bladder cancer, renal cell cancer, colorectal cancer, gliosarcoma, etc.
- (vi)
- Relatlimab, an anti-lymphocyte activation gene 3 (LAG-3) antibody in combination with nivolumab, for the treatment of resectable melanoma [196].
- (vii)
- Lirilumab, an antibody that blocks the killer immunoglobulin-like receptor (KIR)/human leukocyte antigen-C (HLA-C) interaction, for the treatment of patients suffering from myeloid malignancies [197].
4.1.1. Checkpoint Inhibitor Blockade in dMMR-MSI CRCs
4.1.2. Checkpoint Inhibitor Blockade in pMMR-MSS CRCs
4.2. Cellular Immunotherapies
4.2.1. Immunotherapies with CAR T Cells in CRC
- (i)
- NCT03018405 (THINK) using CAR T cells.
- (ii)
- NCT03692429 (alloSHRINK) using CAR T cells after chemotherapy.
- (iii)
- NCT03370198 (LINK) using CAR T cells by hepatic transarterial infusion.
- (iv)
- NCT03310008 (SHRINK) using CAR T cells plus FOLFOX (folinic acid, fluorouracil and oxaliplatin).
- (v)
- NCT04107142 (CTM-N2D-101) using CAR γδ T cells.
4.2.2. Immunotherapies with γδ T Cells in CRC
5. Therapeutic Options: Turning “Cold” CRCs into “Hot” CRCs
5.1. Possibilities to Increase the Infiltration of T Cells
5.1.1. Oncogenic Pathway Inhibitors
5.1.2. Anti-Angiogenic Therapy
5.1.3. TGF-β Inhibitors
5.1.4. CXCR4 Inhibitors
5.2. Enhancement of Neo-Antigens
5.3. Better Priming and Activation of T Cells
5.3.1. Oncolytic Viruses (OVs)
5.3.2. Chemotherapy and Radiotherapy
5.3.3. Cancer Vaccines
5.4. Enhancement of T Cell Trafficking to the Tumor
6. Concluding Remarks
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ACT | Adoptive Cell Transfer |
ALL | Acute Lymphoblastic Leukemia |
APC | Antigen-Presenting Cell |
ATP | Adenosine Triphosphate |
CAF | Cancer-Associated Fibroblast |
CAR | Chimeric Antigen Receptor |
CDK | Cyclin-Dependent Kinase |
CD4 | Cluster of Differentiation Antigen 4 |
CD8 | Cluster of Differentiation Antigen 8 |
CEA | Carcino-Embryonic Antigen |
CIN | Chromosomal Instability |
CMS | Consensus Molecular Subtype |
CRC | Colorectal Cancer |
CRT | Calreticulin |
CTL | Cytotoxic T Lymphocyte |
CTLA-4 | Cytotoxic T-Lymphocyte-Associated Protein 4 |
DC | Dendritic Cell |
dMMR | Mismatch Repair deficient |
DAMP | Damage Associated Molecular Pattern |
DLN | Draining Lymphnode |
DNMTi | DNA Methyltransferase Inhibitor |
EGF | Epidermal Growth Factor |
ERV | Endogenous Retrovirus |
FDA | Food and Drug Administration |
FOXP3 | Forkhead Box P3 |
GZMB | Granzyme B |
HMGB | High Mobility Group Box |
ICB | Checkpoint Inhibitor Blockade |
ICD | Immunogenic Cell Death |
iCMS | intrinsic Consensus Molecular Subtype |
ICR | Immunologic Constant of Rejection |
IDO-1 | Indoleamine 2-3 Dioxygenase-1 |
IEL | Intraepithelial Lymphocyte |
IFN-γ | Interferon-Gamma |
IL-17 | Interleukin-17 |
KRAS | Kirsten Rat Sarcoma Virus Oncogene |
LTR | Long-Terminal Repeats |
mCRC | Metastatic Colorectal Cancer |
mOS | Median Overall Survival |
MDSC | Myeloid-Derived Suppressor Cell |
MHC | Major Histocompatibility Complex |
MHC I | Major Histocompatibility Complex 1 |
miRNA | Micro-RNA |
MMR | Mismatch Repair |
MSI | Microsatellite Instability |
MSS | Microsatellite stable |
ncRNA | Non-Coding RNA |
NF | Nonfibrosis |
NK | Natural Killer Cell |
OV | Oncolytic Virus |
PDAC | Pancreatic Ductal Adenocarcinoma |
pMMR | Mismatch Repair proficient |
PBMC | Peripheral Blood Mononuclear Cell |
PDAC | Pancreatic Ductal Adenocarcinoma |
PD-1 | Programmed Death 1 |
RB | Retinoblastoma |
SBRT | Stereotactic Body Radiotherapy |
SITC | Society for Immunotherapy of Cancer |
STAT | Signal transducer and activator of transcription |
TAM | Tumor-Associated Macrophage |
Tfh | Follicular helper cell |
TGF-β | Transforming Growth Factor Beta |
TGFBR | TGF-β Receptor |
TIM-3 | Mucin-containing protein 3 |
TIL | Tumor-Infiltrating Lymphocyte |
TME | Tumor Microenvironment |
TNF-α | Tumor Necrosis Factor-alpha |
Treg | T Regulatory Cell |
VEGF | Vascular Endothelial Growth Factor |
WNT | Wingless Pathway |
IMGT Database | |
Atezolizumab | https://www.imgt.org/mAb-DB/mAbcard?AbId=526 |
Avelumab | https://www.imgt.org/mAb-DB/mAbcard?AbId=512 |
Bevacizumab | https://www.imgt.org/mAb-DB/mAbcard?AbId=24 |
Ipilimumab | https://www.imgt.org/mAb-DB/mAbcard?AbId=180 |
Lirilumab | https://www.imgt.org/mAb-DB/mAbcard?AbId=423 |
Nivolumab | https://www.imgt.org/mAb-DB/mAbcard?AbId=424 |
Pembrolizumab | https://www.imgt.org/mAb-DB/mAbcard?AbId=472 |
Ramucirumab | https://www.imgt.org/mAb-DB/mAbcard?AbId=295 |
Relatlimab | https://www.imgt.org/mAb-DB/mAbcard?AbId=781 |
Tocilizumab | https://www.imgt.org/mAb-DB/mAbcard?AbId=96 |
Urelumab | https://www.imgt.org/mAb-DB/mAbcard?AbId=373 |
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Name | Surface Marker | Transcription Factor | Polarizing Cytokines | Function | Secreted Cytokines | References |
---|---|---|---|---|---|---|
Th1 | CXCR3+, CCR6− | T-BET | IL-12, IFN-γ | Destruction of infected cells by inducing apoptosis. Th1 cells promote destruction and induce senescence of cancer cells. They also display anti-angiogenic properties. | IFN-γ, TNF-α, IL-2 | [46,47,48] |
Th2 | CXCR3−, CCR4+, CCR6−, CD294+ | GATA | IL-4 | Response to extracellular pathogens. Polarization of macrophages toward a tumor-promoting M2 phenotype. Th2 cells promote the proliferation of tumor cells. | IL-4, IL-5, IL-9, IL-13 | [49] |
Th17 | CXCR3−, CCR4+, CCR6+, CD161+, IL23R+ | IRF4+, ROR-γt+ | TGF-β, IL-6, IL-1β, IL-21, IL-23 | Response to extracellular pathogens by recruiting neutrophils and macrophages to the site of inflammation. Promotion of cancer stemness and chemo-resistance. | IL-17, IL-21, IL-22 | [46,50] |
Th22 | CCR10+, CCr4+, CCR6+ | AHR+, FOXO4+ | IL-6, TNF-α, IL-12, IL-23 | Regulator of epithelial barrier integrity. | IL-22 | [51] |
Tregs | CD127low, CD25+, CTLA4+ | FOXP3+ | TGF-β, IL-2 | Maintain tolerance to self-antigens; prevent the induction of autoantibodies. Suppression of effector T cell-mediated immune responses in colorectal cancer. | IL-10, TGF-β | [46,52] |
Tfh | CXCR5+, ICOS+, PD-1+ | BCL6+ | Orchestration of germinal center B cell responses; required for antibody class switching. | IL-21, IL-4 | [53] |
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Zheng, Z.; Wieder, T.; Mauerer, B.; Schäfer, L.; Kesselring, R.; Braumüller, H. T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment. Int. J. Mol. Sci. 2023, 24, 11673. https://doi.org/10.3390/ijms241411673
Zheng Z, Wieder T, Mauerer B, Schäfer L, Kesselring R, Braumüller H. T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment. International Journal of Molecular Sciences. 2023; 24(14):11673. https://doi.org/10.3390/ijms241411673
Chicago/Turabian StyleZheng, Ziwen, Thomas Wieder, Bernhard Mauerer, Luisa Schäfer, Rebecca Kesselring, and Heidi Braumüller. 2023. "T Cells in Colorectal Cancer: Unravelling the Function of Different T Cell Subsets in the Tumor Microenvironment" International Journal of Molecular Sciences 24, no. 14: 11673. https://doi.org/10.3390/ijms241411673