Here’s What You Want to Know About NKT Cells
What this article covers
- NKT cells, development and classification
- NKT cells were discovered in 1986 and mainly serve as a bridge between innate immunity and adaptive immunity. NKT cells ( natural killer T cells ) are a special subset of T cells that have both T cell receptors (TCR) and NK cell receptors on their cell surfaces.
- 1. Origin and development of NKT cells
- 1 ) . In the thymus, the development process of NKT cells and T cells is very similar.
- 2. Classification, distribution and surface markers
- 1% of peripheral blood T cells. According to TCR type and whether development depends on CD1d molecules, NKT cells are divided into three subtypes: type I NKT cells, type II NKT cells and type III NKT cells.
- 3. Similarities and Differences of Three Types of T Cells
- Nanshan Xiaoxian’s voice-over: NKT is found in small amounts in the blood and contains NK cell receptors as surface markers. Like γδT, it has no MHC restrictions and is cytotoxic, but its main function is immune regulation.
- iNKT cells, anti-tumor function
- NKT cells are the "bridge system" between innate immunity and acquired immunity. NKT cells are an emerging field in tumor immunology.
Our immune system is the best "doctor" in the world. The immune system, on the one hand, recognizes and removes foreign invading bacteria, viruses, etc., and on the other hand, it also removes mutated tumor cells, senescent cells, dead cells or other harmful components in the body.
NKT cells and other immune cells
Immune cells are a huge family. Simply put, NK cells are a type of innate immune cell, CIK is a group of heterogeneous mixed T cells, and NKT is a type of T cell between innate immunity and adaptive immunity . In this popular science article, Xiaoxian will learn about this alternative type of immune cells: NKT cells.
NKT cells, development and classification
NKT cells were discovered in 1986 and mainly serve as a bridge between innate immunity and adaptive immunity. NKT cells ( natural killer T cells ) are a special subset of T cells that have both T cell receptors (TCR) and NK cell receptors on their cell surfaces. NKT cells can produce large amounts of cytokines and can exert cytotoxic effects similar to NK cells. NKT cells express a "semi-constant" TCRαβ peptide chain, which means that the TCRα chain is relatively constant, while the TCRβ chain is diverse, so it is called " NK-like T cell ".
The bridging role of NKT cells
1. Origin and development of NKT cells
NKT cells co-express T cell receptor (CD3) and NK cell receptor ( NK1.1 ) . In the thymus, the development process of NKT cells and T cells is very similar. In the CD4+CD8+ double-positive (DP) selection stage, NKT cells develop independently and undergo CD1d selection (NKT cells interact with glycolipids presented by CD1d ), most develop toward the NKT cell lineage (CD4+NKT or CD4-CD8-NKT) , while CD8+NKT cells do not depend on CD1d.
In addition to CD1d molecules for positive selection, the presence of endogenous glycolipid antigens is also required. Under the selection of glycolipid antigens, the CD1d-glycolipid antigen complex with higher affinity to TCRβ determines the further differentiation of NKT cells.
NKT cell development (mouse)
2. Classification, distribution and surface markers
NKT cells are mainly distributed in the liver, bone marrow, thymus, lungs and other parts of the body, and are in small amounts, accounting for about 0.1% of peripheral blood T cells. According to TCR type and whether development depends on CD1d molecules, NKT cells are divided into three subtypes: type I NKT cells, type II NKT cells and type III NKT cells. Various types of cells are distributed differently and have different effects.
1) Type I: Classic NKT cells, iNKT cells, have constant TCRα receptors. iNKT can only recognize antigens in the presence of CD1d molecules. iNKT cells can specifically recognize α-GalCer , and CD1d/α-GalCer tetramer can be used to label iNKT cells. iNKT cells are the most studied NKT cells and are also commonly considered NKT cells. iNKT cells can differentiate into NKT1, NKT2 and NKT17 subpopulations, similar to Th1, Th2 and Th17 subpopulations.
2) Type II: non-classical NKT cells, lacking constant TCR, can recognize ligands presented by CD1d that are different from α-GalCer. Often found in human bone marrow and liver . Type II NKT cells have immunosuppressive effects and may increase tumor progression and metastasis.
3) Type III: CD1d non-restricted or glycolipid antigen non-reactive subpopulation, most of which are CD 8 positive ; it is a series of highly heterogeneous cells that, in addition to expressing NK1.1 , are more likely to be classified as T Lymphocytes, also known as NKT-like T cells. In type III NKT , there are some CD3+CD56+ cells, which are the main effector cells in the CIK cell population.Nanshan Xiaoxian’s voice-over: The surface markers of NK cells are usually considered to be CD3-CD16+CD56+ , the surface markers of CIK cells are usually considered to be CD3+CD56+ , and the cell surface markers of NK T are usually considered to be CD4- CD8- <here iNKT > .
3. Similarities and Differences of Three Types of T Cells
Nanshan Xiaoxian’s voice-over: NKT is found in small amounts in the blood and contains NK cell receptors as surface markers. Like γδT, it has no MHC restrictions and is cytotoxic, but its main function is immune regulation.
iNKT cells, anti-tumor function
NKT cells are the "bridge system" between innate immunity and acquired immunity. NKT cells are an emerging field in tumor immunology. Compared with NK, CAR-T, TIL and TCR-T, the research and application in tumor immunotherapy lag far behind.
iNKT cells mainly perform anti-tumor immune activity through three mechanisms:
Direct lysis of CD1d-expressing tumor cells
iNKT cells can target tumor cells directly or indirectly. i NKT cells contain a large amount of killer cytokines (such as IL-4, IL-10, IFN-γ, etc.) , which are much higher than NK cells and T cells. When iNKT cells are stimulated, they can quickly release cytokines to kill tumor cells. iNKT cells directly recognize lipid antigens presented by CD1d, thereby stimulating them to produce cytokines, further activating DC cells, NK cells, CD8+T cells and other immune cells to generate a wide range of immune responses. Tumor cells with high CD1d expression are more efficiently lysed by NKT and have a lower probability of tumor metastasis.
iNKT directly targets tumor cells
Lyse immunosuppressive cells expressing CD1d
iNKT cells may also be activated by CD1d+ immunosuppressive cells, including myeloid-derived suppressor cells (MDSC) and tumor-associated macrophages (TAM) .
TAMs are immunosuppressive cells that appear frequently in the tumor microenvironment. TAMs promote tumor progression and inhibit NK cells, iNKT cells, and T cell responses. MDSCs induce inactivation of NK cells and T cells, promoting immune suppression and tumor growth. In addition, TAMs and MDSCs can reshape the tumor microenvironment and increase the metastasis rate. Activation of iNKT cells reduces the number of type II NKT cells (type II NKT cells appear more frequently in the TME, have immunosuppressive effects, and can increase tumor progression and metastasis ) and reduce tumor development and metastasis.
Activate antigen-presenting cells ( such as DC, etc. ).
iNKT cells can not only directly kill tumor cells, but may also be activated by CD1d+APC, playing an important role in anti-tumor immunity . After activation, iNKT cells can secrete a large number of pro-inflammatory cytokines (including IL-2, IL-4, IL-17, IFN-γ, TNF, etc.) and widely affect immune cells (including DCs, macrophages, neutrophils, etc.) , NK cells, and T and B cells) . In addition, activated iNKT cells can actively recruit and induce DC maturation.
Figure 5. iNKT activates APC
Due to the important role of NKT cells in immune monitoring and anti-tumor immunity, NKT cell tumor immunotherapy is also a current research hotspot, with 7 strategies:
1. Administer free α-GalCer alone
2. Adoptive transfer of α-GalCer-presenting DC cells
3. Adoptive transfer of activated iNKT cells
4.As a cancer vaccine adjuvant
5. CD1d antibody fusion protein
6. CAR-NKT cells
7. Combination therapy with chemotherapy, oncolytic viruses, and immunotherapy
Nanshan Xiaoxian's voice-over: 1)NKTcells exist in normal tissues and tumors, facilitating the generation of immune responses in solid tumors. 2) By inducing a variety of immune responses, it can produce therapeutic effects on a variety of tumors and can theoretically be used as a broad-spectrum treatment. 3) Derived from natural cells, does not change genes, has minimal side effects on the body, and will not affect the survival of normal cells.
Global NKT cell therapy clinical research
Due to their potent and broad anti-tumor activity, good safety profile and potential for allogeneic use, NKT cells are highly focused candidates in various cancer immunotherapy approaches. Many companies around the world have set their sights on NKT cells for anti-tumor use, and are promoting NKT cell anti-tumor research at different levels and pushing them into clinical trials.
Among them, foreign companies have made rapid progress in research and development, and registered clinical trials of NKT therapies are mainly concentrated in the 1/2 phase, including MiNK , Athenex/Kuur, Appia Bio/Kite, Arovella, etc.; while domestically, NKT clinical trials developed by GeneqiMing The IND application for the therapeutic product " GKL-006 Injection " was accepted.
Overview of NKT clinical trials conducted globally
In addition to the commercial development of NKT cell products, some laboratories also conduct NKT cell research . For example, the iPS Cell Research Institute ( CiRA ) of Kyoto University in Japan is developing iPSC-NKT cells to treat head and neck cancer; Texas Children's Hospital in Houston is developing CAR-NKT cells to treat neurocytoma; Lu, director of the Department of Medical Oncology at Beijing You'an Hospital affiliated to Capital Medical University, Professor Jun conducts iNKT cell therapy for liver cancer; Professor Zhang Minghui of Tsinghua University School of Medicine conducts research on NKT cell therapy for tumors.
Nanshan Xiaoxian's voiceover: The news is not all good. In 2023,the productKUR-501(CAR-NKT)developed bythenexclinically suspendedthe FDA. In addition, the launch of oral paclitaxel was also rejected by the FDA, and its cash flow dried up.Athenex had no choice but to file for bankruptcy and could only "sell itself to pay off debts" and find buyers for NKT cell therapy.
Summary at the end of the article
NKT cell therapy is considered a "niche" cell therapy ( compared to NK, CAR-T , TIL and TCR-T ) . iNKT cells play an important role in immune surveillance and anti-tumor immunity. iNKT cell therapy lasts longer and is more capable of inhibiting the recurrence and metastasis of cancer. It may become an important treatment method for cancers such as solid tumors.
With the continuous breakthroughs in immune cell technology for treating solid tumors, the NKT cell immunotherapy industry will develop rapidly. It is believed that NKT cell-based immunotherapy will shine in the future.
Finally, several questions remain to be answered regarding NKT cells :
- What are the most promising indications for NKT cell immunotherapy?
- How to solve the problem of insufficient expansion of NKT cells
- Could the complex TME in solid tumors be an obstacle to NKT cell efficacy in solid tumors?
- Problems with persistence and maintenance of activated state of NKT cells after adoptive transfer?
- Do NK T cells have an advantage in resolving immune evasion?
Key Questions Answered
- What are NKT cells and how do they function in the immune system?
- NKT cells are a special subset of T cells that bridge innate and adaptive immunity, possessing both T cell and NK cell receptors. They can produce large amounts of cytokines and exert cytotoxic effects similar to NK cells. NKT cells play an important role in immune surveillance and anti-tumor immunity by recognizing lipid antigens and activating other immune cells.
- What are the different classifications of NKT cells?
- NKT cells are divided into three subtypes: type I, type II, and type III. Type I NKT cells, also known as iNKT cells, have constant TCRα receptors and recognize antigens presented by CD1d molecules. Type II NKT cells are non-classical, lack constant TCR, and can have immunosuppressive effects, potentially increasing tumor progression. Type III NKT cells are CD1d non-restricted or glycolipid antigen non-reactive, often CD8 positive, and are a highly heterogeneous group.
- How do iNKT cells fight tumors?
- iNKT cells primarily perform anti-tumor immune activity through three mechanisms. They can directly lyse CD1d-expressing tumor cells by releasing killer cytokines. They may also be activated by CD1d+ immunosuppressive cells, such as myeloid-derived suppressor cells and tumor-associated macrophages, reducing their numbers. Additionally, iNKT cells can activate antigen-presenting cells like dendritic cells, secreting pro-inflammatory cytokines that widely affect other immune cells.
- What is the status of NKT cell therapy in clinical development?
- NKT cell therapy is a current research hotspot, with many companies globally promoting NKT cell anti-tumor research into clinical trials. Registered clinical trials for NKT therapies are mainly concentrated in Phase 1/2, with foreign companies like MiNK, Athenex/Kuur, and Appia Bio/Kite making rapid progress. Domestically, an IND application for the therapeutic product "GKL-006 Injection" was accepted. However, there have been setbacks, such as Athenex's KUR-501 (CAR-NKT) product facing clinical suspension by the FDA in 2023.
Sources
- No external citations were included in the original source material for this article.
Related Articles
- Clinical Applications
What Does the FDA's CAR-T Boxed Warning on Secondary Cancers Actually Show?
The FDA's 2024 class-wide boxed warning on secondary T-cell cancers after CAR-T flagged a real signal — but the largest datasets since show the absolute risk is low and CAR-T's benefits still outweigh it.
- Clinical Applications
Why Doesn't Immunotherapy Work Well for Pancreatic Cancer? What the Evidence Shows
Most pancreatic tumors are genetically quiet and walled off by dense stroma, so checkpoint inhibitors rarely work — except in the small MSI-H/dMMR subset. Personalized mRNA vaccines are the most promising lead.
- Clinical Applications
FDA Grants Breakthrough Therapy Designation to WU-CART-007 for Relapsed T-Cell Leukemia and Lymphoma: What the Phase 1 Data Show
An off-the-shelf CD7-targeted CAR-T produced a 91% response rate in evaluable Phase 1 patients — in cancers with no new FDA-approved therapy since 2005.