May 28, 2024

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What are the prerequisites for immunotherapy to be effective?

What are the prerequisites for immunotherapy to be effective?



 

What are the prerequisites for immunotherapy to be effective?

NRCO authoritative review: Cleveland Clinic’s experts provide a detailed explanation of the crucial antigen presentation machinery in immunotherapy!

 

The correct recognition and processing of tumor antigens, followed by their presentation to immune effector cells such as CD8+ cytotoxic T cells, is the crucial prerequisite for the successful completion of the antigen presentation machinery (APM).

 

If the antigen presentation process is not smooth, the anti-tumor immune response will be in the dark, unaware of the identity and location of the enemy.

In such cases, it becomes challenging to achieve victory in immunotherapy. Unfortunately, the occurrence and progression of malignant tumors often involve problems with the APM process, requiring targeted interventions.

 

In a recent article published in “Nature Reviews Clinical Oncology,” renowned figure in the field of immunotherapy, Timothy A. Chan, along with colleagues from the Cleveland Clinic, provided an in-depth analysis of the molecular and genetic regulatory mechanisms related to antigen presentation in the process of immunotherapy. They also analyzed the impact of these mechanisms on the outcomes of immunotherapy. [1]

 

What are the prerequisites for immunotherapy to be effective?

Screenshot of paper home page

 

 

 


Mechanism of tumor cell antigen presentation

 

When it comes to antigen presentation, the concept of MHC-major histocompatibility complex must not be avoided. MHC in the human body is mainly divided into two types: MHC-I and MHC-II. Their coding genes and structures are different. In addition, There are also the following differences:

 

MHC-I exists on the surface of nucleated cells, binds to a binding peptide with a length of 8-11 amino acids, and is then recognized by the T cell receptor (TCR) of CD8 + T cells;

 

MHC-II exists on the surface of antigen-presenting cells and hematopoietic cells, and its binding peptide is relatively longer (10-16 amino acids) , and the MHC-II complex is mainly recognized by CD4 + helper T cells.

 

 

 

What are the prerequisites for immunotherapy to be effective?

Difference Between MHC-I and MHC-II

(Image source: Journal of Hematology & Oncology)

 

 

 

Antigen processing and presentation in cancer cells revolves around MHC-I molecules. The specific process can be divided into three steps, namely:

1) The antigen protein is degraded by protease and converted into a polypeptide with a length of 9-16 amino acids;

2) The antigen polypeptide is transported to the endoplasmic reticulum, and after further tailoring and the action of endoplasmic reticulum aminopeptidase 1 (ERAP1) and other enzymes, it is assembled into an MHC-class I molecule-polypeptide complex; 3) the complex is transported to Cell surface expression.

 

 

 

What are the prerequisites for immunotherapy to be effective?

Antigen processing and presentation in cancer cells

 

 

 

Next, professional antigen-presenting cells (APCs) such as dendritic cells (DCs) will ingest MHC-I antigens through endocytosis/endocytosis/cytosis, etc.

The cytosolic/vacuolar pathway is processed, which is the key to further activation of naive CD8 + T cells , and the antigen cross-presentation (Cross-Presentation) mediated by DCs is of great significance to immunotherapy[2].

 

 


“Change” in antigen presentation mechanism

 

If the antigen presentation mechanism can be successfully completed, then CD8 + cytotoxic T cells will accurately migrate to the tumor site, effectively recognize MHC-I antigens and kill cancer cells, but things are not always so simple, various influencing factors, such as encoding Genetic variation, transcriptional and post-translational regulation, and epigenetic changes in MHC-I molecules or other APM components can affect the activation of immune responses by antigen presentation.

 

HLA allelic variation

There are strong polymorphisms in the HLA – A / B / C gene encoding the heavy chain of MHC-I molecules , and the HLA phenotype of each patient will have an impact on the antigen presentation process and immunotherapy response.

A landmark study in Science showed that the stronger the heterozygosity of the HLA gene in patients with non-small cell lung cancer (NSCLC), the greater the possibility of benefiting from immune monotherapy [3], and there are many follow-up studies similar conclusions were obtained.

 

Some specific HLA supertypes (Supertype) can also be used to predict the response to immunotherapy.

For example, in melanoma patients, HLA-B44 supertype is associated with longer overall survival (OS) after immunotherapy, and HLA-B62 supertype It is associated with shorter OS, and the reason may be that HLA supertype affects the interaction between TCR and MHC-I molecules; the biomarker also involved in the antigen presentation process is HLA loss of heterozygosity (HLA LOH).

 

Regulation of HLA expression

Many regulatory mechanisms in transcription, translation and post-translation can affect HLA expression, thereby affecting the antigen presentation process.

For example, interferon-γ (IFNγ) can activate interferon regulatory factor 1 (IRF1) to stimulate NLRC5 by activating the JAK – STAT pathway The expression of HLA-A / B / C genes is up-regulated , which affects the activation of CD8 + T cells and even the prognosis of patients.

 

There are many transcription factors or signaling pathways that have similar regulatory effects to IFNγ, and various miRNAs can also regulate the expression of HLA genes after transcription; after MHC-I molecules are translated, cancer cells can also undergo autophagy. , endoplasmic reticulum-related degradation and other pathways, reducing the expression of MHC-I molecules on its own surface.

 


Changes in other components of the antigen presentation process

 

In addition to HLA genes, multiple genes related to the process of processing, transporting and presenting antigenic epitopes (Epitope) may also be mutated .

Abnormal expression of MHC-I molecules on the cell surface will affect antigen presentation and anti-tumor immune response.

 

Epigenetic and epitranscriptional regulation

Epigenetic silencing is one of the important mechanisms to reduce HLA expression and promote immune escape during the development of cancer.

For example, hypermethylation of HLA gene promoter regions common in digestive system cancers is related to down-regulation of MHC-I molecules, antigenic Submission limitations are related, but the research in this field is not very in-depth.

 

 

 

What are the prerequisites for immunotherapy to be effective?

A graph summarizing changes related to various antigen presentation mechanisms

 

 


Relationship between antigen presentation process and clinical response to immune checkpoint inhibitors

 

Some available markers related to the antigen presentation process have been introduced above, such as HLA gene heterozygosity, HLA supertype, etc. Similar markers include HLA evolutionary diversity (HED), which are often associated with tumor mutations.

Burden (TMB) and other known markers are used in combination to improve prediction performance [4]; with the help of machine learning technology, the academic community also analyzed the relationship between HLA allelic variation characteristics and immunotherapy response.

 

Analysis of data from The Cancer Genome Atlas Project (TCGA) shows that most immunogenic tumors have upregulation of HLA class I genes, and the “immunoinflammatory” tumors with the best immunotherapy effects are often accompanied by upregulation of HLA class II genes.

The lack of expression of MHC-I molecules often indicates that the effect of immunotherapy is not good.

 

However, many studies in recent years have shown that CD4 + T cells can also recognize MHC-II antigens on the surface of some tumor cells, thereby activating a certain degree of anti-tumor immune response.

This effect of CD4 + T cells has long been recognized. Underestimated, so improving the presentation of MHC-II antigens is indeed a therapeutic idea. In addition, the impact of chemotherapy and other means on the antigen presentation process in combined immunotherapy is also worthy of further exploration.

 

 

 

How to guide immunotherapy with the help of antigen presentation process

 

After PD-1/L1 inhibitors and CTLA-4 inhibitors, many inhibitors targeting other immune checkpoints are gaining momentum, and their impact on the antigen presentation process also needs to be elucidated.

In immunotherapy in a broad sense, such as CAR-T cell therapy and TCR-T therapy, the participation of antigen presentation is also indispensable, so I won’t go into details here.

 

 


Summary

The significance of antigen presentation in activating T cells and immunotherapy response is beyond doubt.

However, the regulatory mechanisms involved in this process are extremely complex, and our current understanding in the academic field may only scratch the surface.

It is believed that with continuous in-depth research exploration, clinical practitioners will be able to precisely guide the use of immunotherapy based on the dynamic changes in antigen presentation process in the future.

 

 

 

 

 

 

references:

[1] Yang K, Halima A, Chan T A. Antigen presentation in cancer—mechanisms and clinical implications for immunotherapy[J]. Nature Reviews Clinical Oncology, 2023.

[2]Sánchez-Paulete AR, Teijeira A, Cueto FJ, et al. Antigen cross-presentation and T-cell cross-priming in cancer immunology and immunotherapy[J]. Annals of Oncology, 2017, 28: xii44-xii55.

[3]Chowell D, Morris LGT, Grigg CM, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy[J]. Science, 2018, 359(6375): 582-587.

[4]Chowell D, Krishna C, Pierini F, et al. Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy[J]. Nature Medicine, 2019, 25(11): 1715-1720.

What are the prerequisites for immunotherapy to be effective?

(source:internet, reference only)


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