Nature's heavy review 2: The role of antigen presentation in tumors

‍‍Hello everyone, today I will introduce to you a review article published in Nature Reviews Cancer in 2021, titled "Antigen presentation in cancer: insights into tumour immunogenicity and immune evasion".
This article is about tumor-derived factors that regulate DC cells.
To summarize, and summarize the evidence of immune escape by regulating tumor antigens.

These mechanisms include regulating antigen expression, HLA-1 surface level, and altering the mechanism of antigen processing and presentation in tumor cells.

Finally, since complete elimination of antigen presentation can lead to natural killer (NK) cell-mediated tumor killing, the authors also discussed how tumors can hide antigen presentation defects and still evade NK cell recognition.

Because there is too much content, I only summarize the key content here, and interested friends can read the full text! By blocking immune checkpoints, the inhibitory signal of T cell activation can be blocked, and cancer can be effectively treated, although it is limited to some patients.

So far, clinically effective CD8+ T cell responses appear to be mainly directed at antigens derived from tumor-specific mutations that accumulate in cancer and are also called neoantigens.

Tumor antigens are displayed on the cell surface through Class I human leukocyte antigen (HLA-1).

In order to elicit an effective anti-tumor response, antigen presentation must be successful in two different events: First, the cancer antigen must be taken up and presented by dendritic cells (DC) for the initiation of CD8 + T cells.

Second, the antigen must be directly presented by the tumor in order to be recognized and killed by activated CD8 + T cells.

In these two steps, tumors can use multiple escape mechanisms to evade immune recognition.

Here, we summarize the tumor-derived factors that regulate DC function, and evade immune evidence by quantitatively regulating or qualitatively changing tumor antigens.

These mechanisms include regulating antigen expression, HLA-1 surface level, and altering the mechanism of antigen processing and presentation in tumor cells.

Finally, since complete elimination of antigen presentation can lead to natural killer (NK) cell-mediated tumor killing, the authors also discussed how tumors can hide antigen presentation defects and still evade NK cell recognition.

 Background Introduction CD8+ T cells are the main cells of anti-cancer immunity, and regulating the response of CD8+ T cells has always been the focus of immunotherapy for cancer.

When CD8+ T cells specifically recognize antigen peptides presented by the major histocompatibility complex (MHC; in vertebrates) or human leukocyte antigen (HLA; in humans) on tumor cells, they can be activated and kill the tumor cell.

Due to the presence of inhibitory signals at the tumor site, tumor-specific T cells usually exhibit dysfunction.

In some patients, elimination of these inhibitory signals through immune checkpoint inhibition (ICI) can lead to reactivation of T cells and improve clinical efficacy.

The existence of other immunosuppressive factors and the reduction of tumor cell antigen presentation can explain the limitation of T cell activity.

In fact, studies have shown that tumors have advanced different methods to limit HLA-1 presentation of antigens and evade immune recognition.

Cancer rejection antigens are the targets of anti-tumor T cells.

Such rejection antigens include tumor-associated antigens (TAA), viral antigens and tumor-specific antigens (TSA), and are very important for the development of antigen-targeted tumor immunotherapy.

With the advent of ICI, the use of a powerful vaccine platform to combine with ICI, or the use of rare high-affinity T cell receptors (TCR) for adoptive T cell therapy or T cell redirection bispecific molecules have reinvigorated people’s interest in TAA interest.

Therapeutic vaccination against human papillomavirus (HPV) has been effective in HPV-induced cancers.

Most TSAs are neoantigens and can be produced by many types of tumor genome aberrations.

Neoantigens are present in most tumors and are related to the clinical response to ICI and adoptive T cell therapy.

Early clinical trial results of neoantigen-specific cancer vaccines have shown that it will cause neoantigen-specific T cell responses, but it is not clear whether these responses are clinically effective.

The challenge with targeting neoantigens is that they are usually specific for each patient and require the development of an individualized approach called neoantigen-specific immunotherapy (iNeST).

Cancer rejection antigens presented by HLA-1 are essential for immunotherapy to stimulate anti-tumor CD8 + T cell responses (including ICI and iNeST), and it is also important to understand the extent of HLA-1 presentation defects in tumors.

In order to elicit an effective anti-tumor response, antigen presentation must be successful in two different events.

First, cancer antigens must be taken up and presented by dendritic cells (DC) for CD8 + T cell activation.

Second, the antigen must be directly presented by the tumor in order to be recognized and killed by activated CD8 + T cells.

Of course, tumors will also develop a variety of mechanisms to reduce the antigen presentation of these two key steps, thereby avoiding antigen recognition, including inhibiting the function of DC cells, interfering with antigen processing and presentation mechanisms to reduce tumor cells’ HLA-1 Expression (APM; Figure 1).

Without completely eliminating the surface expression of HLA-1, tumors have also developed more sophisticated immune escape strategies.

A better understanding of how tumors reduce the HLA-1 presentation of rejection antigens will provide evidence for the application of antigen presentation-based immunotherapy.

Tumors can also present antigens on HLA-II to be recognized by CD4 + T cells, and this pathway may also be regulated by immune escape.

Figure 1.
Antigen processing and presentation Dendritic cell (DC) deficiency DC plays a central role in the initiation and maintenance of anti-tumor T cell immunity. When tumor cells are processed into damage-related molecular patterns (DAMPs), DC cells gradually mature and migrate to lymph nodes, process and load cancer antigens on HLA-1, and present them to CD8 + T cells.

DCs also up-regulate costimulatory molecules and produce pro-inflammatory cytokines, which are essential for the full activation of naive T cells.

Among various DC cell subgroups, cDC1s play a vital role in anti-tumor immunity.

Batf3 knockout mice lacking cDC1 cannot activate anti-tumor CD8 + T cells and respond to ICI.

The number of cDC1 in the tumor microenvironment (TME) is related to T cell infiltration, the overall survival rate of cancer patients, and the response to ICI.

In addition to playing a role in lymph nodes, cDC1s is essential for the activation of circulating central memory T cells and their differentiation into tissue-resident memory CD8 + T cells in mouse tumors and their response to ICI.

Since cDCs play a major role in activating anti-tumor T cell responses, they are the "anti-target" of tumors and can evade the activation of the adaptive immune system (Figure 2).

Figure 2 Anti-tumor immune response of DC cells When tumor cells are processed into DAMPs, immature cDC1 cells will gradually mature and migrate to lymph nodes, and at the same time deliver tumor antigens to activate naive CD8 + T cells.

Tumors have developed a variety of ways to inhibit DC maturation and function.

Necrotic tumor cells release high levels of PGE2, thereby inhibiting the immunostimulatory activity of DAMPs on macrophages and DC in vitro.

The release of vascular endothelial growth factor (VEGF) from tumor cells can affect DC differentiation and maturation.

TME also actively produces cytokines that interfere with the maturation of DCs, such as IL-6, transforming growth factor-β (TGFβ) and IL-10, thereby promoting the transformation of DCs into a tolerogenic phenotype.

In addition to maturation defects, studies have shown that cDC1s in tumors may exhibit impaired cross-expression.

Increased levels of oxidized lipids in DC are related to defects in cross-presentation.

Therefore, tumors can trans-regulate their antigenicity by changing the functions of tumor-related DCs.

DC cells in tumors may have dysfunction, tolerance and even immunosuppressive phenotypes.

By targeting DC cells, cancer vaccines can help overcome some of these shortcomings and effectively promote T cell activation.

In addition, in situ vaccines are also under development and show encouraging results.

Presenting effective adjuvants, such as polyinosinic acid: polycytidylic acid (poly(I:C)), Toll-like receptors or STING agonists, can overcome certain immunosuppressive signals at the tumor site and induce DC maturation.

VEGF blocking therapy can also help promote DC differentiation and function.

In tumors with low DC infiltration, it may be necessary to combine this treatment with FLT3L treatment to increase the number of cDC1 in the tumor, and combine it with radiotherapy, chemotherapy, and even adoptive T cell therapy to enhance tumor cell death and promote cDC1s Provide tumor antigens.

 HLA-I defects in tumors are triggered by cDC1s, CD8 + T cells metastasize from lymph nodes to tumors, where they recognize and kill antigens directly presented on HLA-1 by tumor cells.

In addition to restricting the DC function initiated by T cells, there are also changes in the antigen presentation pathway in tumors, which can also cause CD8 + T cells to fail to recognize.

The peptide presentation of HLA-1 involves many processes.

The HLA-1 complex on the cell surface is composed of three parts: HLA-1 heavy chain, β2-microglobulin (β2m) and 8-12 amino acid peptide derived from endogenous protein.

The HLA-1 complex itself is a component of APM and participates in the process of HLA-1 presentation of peptides (Figure 1).

The proteasome is the main enzyme complex that processes cellular proteins into peptides, which are then transported to the ER by the ATP binding cassette transporters TAP1 and TAP2 (or collectively referred to as TAP).

Peptide loading on HLA-1 occurs in the ER and is assisted by several accessory proteins and molecular chaperones in the peptide loading complex (PLC).

Once a stable HLA-1 peptide complex is formed, it can be transferred to the cell surface.

Although all nucleated cells constitutively display peptide-HLA-I complexes on their surface, antigen presentation can be upregulated in an inflammatory environment, mainly by activating the cytokine IFNγ produced by lymphocytes.

IFNγ receptor signaling through the JAK-STAT signaling pathway can induce a variety of APM components, including cis or trans HLA-1 heavy chain and β2m (Figure 3a).

This circuit can enhance the immune response, and enhance the recognition and lethality of target cells.

Tumors can reduce antigen presentation on their surface through a variety of mechanisms, including antigen depletion, reduction of HLA-1 surface expression through genetic changes, regulation of transcription, and changes in HLA-1 peptide repertoire and other groups of APM by changing HLA-1 genes.
Minute.

 Figure 3.
Regulation of antigen presentation in tumors.
Antigen exhaustion.
Cancer rejection.
Antigen exhaustion may be a tumor immune escape mechanism, especially if the antigen is a by-product of tumorigenesis and is not essential for tumor cell survival.
in the case of.

Some TAAs are by-products of dysregulated expression of their coding genes, and most neoantigens are derived from "passenger mutations.
"
Antigen depletion in tumors may occur through copy number loss at the genome level, down-regulation of RNA expression caused by epigenetic or post-translational mechanisms (Figure 3a).

Loss of TAA was also observed between different lesions in the same patient.

There is emerging evidence that under immune pressure, tumors can lose neoantigens at the DNA and RNA levels.

 Compared with wild-type, tumors in untreated non-small cell lung cancer (NSCLC) patients are hypermethylated at the promoters of genes encoding unexpressed neoantigens.

In addition, in these patients, tumors with high levels of immune infiltration are unlikely to express neoantigen-encoding genes.

 In addition to regulating gene expression, tumors can also regulate protein renewal, thereby regulating the presentation of new antigens.

Recently, Jaeger and colleagues discovered that tumors can "hide" the mutant protein in the antigen presentation pathway by stabilizing the mutant protein with HSP90.

The loss of effective neoantigens may become a refractory mechanism of anti-tumor immunity and pose a challenge to iNeST.

ICI found in several patients with high tumor mutation burden that neoantigen depletion as a mechanism of immune escape may not be comprehensive.

 Genetic changes in HLA-1 and B2M HLA-1 heavy chain and β2m are the core components of the HLA-1 complex that presents peptides.

Cells can express three genes (HLA-A, HLA-B and HLA-C), six different HLA-1 alleles, and each gene provides a unique set of peptides.

It has been described in its coding genes that it can lead to reduced or complete loss of peptide presentation.

These genetic events may have different effects on the degree and diversity of HLA-1 presentation.

Since β2m is a component of all HLA-1 allotypes, heterozygous deleterious mutations or LOH of B2M can cause the surface expression level of HLA-1 to decrease.

A deleterious mutation on one allele plus complete copy number loss of LOH or B2M is necessary for the apparent complete loss of HLA-1.

On the other hand, due to the different composition of different HLA-1 allotypes, the loss of a subset of HLA-1 allotypes is likely to reduce the diversity of the peptide library presented.

Understanding the incidence of these events is very important for assessing the frequency of possible loss of antigen presentation in different cancer indications and for designing appropriate immunotherapy strategies.

Except for HLA-1 and β2m, changes in genes encoding other APM components are not common.

Our analysis of the TCGA database showed that about 3% of the 10967 cancer patients analyzed had changes (Figure 3b).

Changes in HLA-1 peptide library Changes in APM components in tumors may change the peptide spectrum that certain HLA-1 complexes can present, rather than reduce HLA-1 surface expression.

Although the altered peptide library may increase immunogenicity, DCs with unaltered APM may not necessarily exhibit such altered peptides.

Therefore, T cells may not be able to activate against this altered component, and tumor immune evasion may occur.

 Recognition of tumors by NK cells NK cells are part of the innate immune system.
Here, we focus on the importance of NK cells in monitoring and counteracting the reduction in antigen presentation or in regulating tumor immunogenicity.

In principle, the loss of HLA-1 should lead to NK cell-mediated tumor cell killing, but several factors may jointly determine the efficiency of this process: first, the differential distribution of NK cell subpopulations in different tissue types; second, they are The abundance in tumors; third, tumor immune evasion strategies can regulate the effectiveness of NK cells, activation or self-deleting recognition (Figure 4); fourth, the immune genetic composition of the patient’s genome.

 Figure 4.
The effect of HLA-1 loss on natural killer cell activity and tumor immune escape.
As shown in Figure 4, several tumor escape strategies have been described that interfere with the effectiveness of NK cells in cancer.

Conclusion Cancer immunotherapy has shown encouraging success, but many patients still do not respond to the therapy.

Understanding the biological mechanisms of cancer immunity or escape will provide options for new immunotherapies, combination therapies and the identification of biomarkers.

Many immunotherapies rely on CD8 + T cells to recognize and kill tumor cells.

These immunotherapies not only rely on the initiation of endogenous T cells by DCs in tumors, but also on the presentation of tumor antigens by HLA-1 displayed on tumor cells.

Although no comprehensive research has been conducted on all cancer types, reports published so far indicate that the surface expression of HLA-1 can be extensively regulated by a variety of mechanisms.

In addition, early evidence suggests that tumors may combine multiple mechanisms to reduce the presentation of HLA-1.

The enrichment of HLA-1 and B2M LOH and other changes in patients who did not respond to ICI suggest that HLA-1 has a certain effect in reducing drug resistance.

However, ICI can still work in patients with some of the same changes.
This fact suggests that, especially for tumors with high mutation burdens, this manipulation of antigen presentation by tumors may not be complete.

For patients with irreversible damage to antigen presentation, CD8 + T cell-dependent immunotherapy may not be a suitable choice.

These patients should use other tumor immunotherapy independent of HLA-1 expression, such as activation of NK cells or killer macrophages, synthetic immunity (such as CAR-T cell therapy and CD3 bispecific antibodies) or other traditional cancer treatments .

For other patients whose antigen presentation is reversibly down-regulated, it is necessary to design strategies to restore antigen presentation on tumor cells, and these strategies may be beneficial in combination therapy with ICI.

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