Tumor antigens recognized by T lymphocytes

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Fig. 1. Processing of tumor antigens recognized by CD8 T cells Processing of tumor antigens recognized by CD8+ T cells.jpg
Fig. 1. Processing of tumor antigens recognized by CD8 T cells

T lymphocytes are cells of the immune system that attack and destroy virus-infected cells, tumor cells and cells from transplanted organs. This occurs because each T cell is endowed with a highly specific receptor that can bind to an antigen present at the surface of another cell. The T cell receptor binds to a complex formed by a surface protein named "MHC" (major histocompatibility complex) and a small peptide of about 9 amino-acids, which is located in a groove of the MHC molecule. This peptide can originate from a protein that remains within the cell (Fig. 1). Whereas each T cell recognizes a single antigen, collectively the T cells are endowed with a large diversity of receptors targeted at a wide variety of antigens. T cells originate in the thymus. There a process named central tolerance eliminates the T cells that have a receptor recognizing an antigen present on normal cells of the organism. This enables the T cells to eliminate cells with "foreign" or "abnormal" antigens without harming the normal cells.

Contents

It has long been debated whether cancer cells were bearing "tumor-specific" antigens, absent from normal cells, which could, in principle, cause the elimination of the tumor by the immune system. It is now proven that tumor-specific antigens exist and that patients mount spontaneous T cell responses against such antigens. Unfortunately, it is clear that in many and perhaps most instances this response is insufficient to prevent cancer progression and metastasis. The purpose of T cell-mediated cancer immunotherapy is to reactivate these responses to a degree that results in tumor destruction without causing harmful effects on normal cells.

Processes leading to the presence of tumor-specific antigens on cancer cells

Gene mutations

As cancer progresses, the genome of cancer cells accumulates point mutations and other genetic abnormalities. Some point mutations result in an amino-acid change in a protein. This can result in the presentation of a new peptide by an MHC molecule. [1] [2] In some instances, the normal sequence does not enable the peptide to bind to a MHC molecule whereas the new peptide does. Hence, a new antigen is present only on the tumor cells. In other instances, the normal peptide is presented at the cell surface and consequently the T lymphocytes that recognize the antigen have been eliminated by the central tolerance process that occurs in the thymus. The mutated peptide is recognized by other T cells which have not been eliminated by central tolerance because it is not presented by normal cells.

Genetic processes other than point mutations can lead to tumor-specific antigens. An interesting example is gene fusions resulting from specific chromosomal translocations frequently encountered in certain types of cancer. The gene fusion produces a chimeric protein segment from which a new antigenic peptide can be derived.

The recognition of mutation-induced antigens on tumors by T cells is only one aspect of a more general phenomenon which can rightly be named: T cell immunosurveillance of the integrity of the genome. Any somatic mutation has a probability of producing a new antigen that can be recognized by T cells. If the mutated cell divides significantly, the resulting clonal population may be eliminated by a T lymphocyte response.

Tumor-specific gene expression

Some genes are expressed by tumor cells and not by normal cells. A class of genes, named cancer-germline genes, is expressed in a large variety of cancer cells but not in normal cells, with the exception of germline cells, which do not carry MHC molecules on their surface and therefore do not present the antigens. [3] [4] Antigenic peptides derived from the encoded proteins are therefore presented on the surface of tumor cells and not on normal cells.

Oncogenic viruses

Some viruses have the ability to transform normal cells into cancer cells. Human oncoviruses include human papilloma virus, Epstein-Barr virus or Kaposi sarcoma-associated virus. The transformed cells often express permanently some viral genes. This leads to the presentation of viral antigenic peptides absent from normal cells.

Tumor antigens targeted by spontaneous T cell responses of cancer patients

Antigens produced by gene mutations

Mutated genes contribute greatly to the immunogenicity of human tumors. In cancer patients, about one half of the highly tumor-specific antigens recognized by spontaneous T cell responses are encoded by mutated genes, the other half being encoded by cancer-germline genes. [5] In some patients, the majority of the tumor-specific T cells recognize mutated antigens. [6] The contribution of these antigens to tumor immunogenicity is expected to vary according to the mutation rate: higher in lung carcinomas arising in tobacco smokers, in melanomas owing to mutations induced by UV and in the 15% of colorectal carcinomas that have hypermutated DNA owing to defects in the DNA mismatch repair pathway. [7]

Antigens produced by cancer-germline genes

Cancer-germline genes are an important source of tumor-specific antigens. These genes are expressed in a significant fraction of tumors of many different histological types. They are not expressed in normal adult cells with the exception of male and female germline cells. But the expression of cancer-germline genes in germ cells is inconsequential because in the healthy state these cells are devoid of HLA class I molecules and therefore cannot present antigens to T cells. Therefore, the antigens of cancer-germline genes are presented to T lymphocytes only on tumor cells. The mechanism leading to the activation of these genes in tumor cells involves the demethylation of their promoter which is methylated in all normal cells except germline cells. [8] [9] Important families of such genes are the MAGE family (25 genes), BAGE, GAGE and LAGE/ESO-1 [2]

Melanocyte differentiation antigens

Unexpectedly, spontaneous T cell responses to differentiation antigens have been well documented in melanoma patients, with T cells recognizing tumour cells and normal melanocytes. The main antigenic peptides recognized by such CTL are derived from tyrosinase, Melan-A (also known as MART-1), and gp100. [5] The reason why tolerance against these melanocytic antigens is incomplete is unknown. In some patients this response leads to vitiligo, i.e. elimination of patches of normal melanocytes. But in most patients it does not.

Oncoviral antigens

A number of viruses named oncoviruses cause cancer. These are mainly human papilloma virus (HPV) causing cervical carcinoma, and Epstein-Barr virus causing B cell lymphomas and nasopharyngeal carcinomas. Kaposi sarcoma virus and Merkel cell polyoma virus cause skin cancers. Human T-lymphotropic virus (HTLV) causes T cell leukemias. Hepatitis B (HBV) and C (HCV) viruses cause chronic inflammation which favors the appearance of hepatocarcinoma. The carcinoma cells still harbour the viral genes and antigens. As expected T cell responses against antigens encoded by genes of these viruses are observed.

Fig. 2. Classes of human tumor antigens recognized by T lymphocytes, with their genetic process Classes of human tumor antigens recognized by T lymphocytes, with their genetic process.jpg
Fig. 2. Classes of human tumor antigens recognized by T lymphocytes, with their genetic process

Targeting tumor antigens in cancer immunotherapy

Cancer therapy targeted at tumor antigens can involve the direct use of these antigens in vaccines, but also the adoptive transfer of T cells that recognize these antigens. Finally, antibodies that increase the general activity of T cells appear to be very efficacious in activating antitumoral T cells.

Vaccines

Tumor-specific antigens encoded by mutated genes were considered to be unsuitable for vaccines because they are different for every patient. However, these are very promising antigens and the progress in genome sequencing appears now to make it possible to identify such antigens for individual patients and use them as personalized vaccines.

Antigens encoded by cancer-germline genes such as MAGEA1 and MAGEA3 have been used in the form of antigenic peptide, protein or recombinant viruses harbouring a sequence coding for the antigen. Clinical responses have been observed in a small minority (< 10%) of patients. However, so far, large randomized trials have failed to demonstrate significant benefit to the patients.

Melanocytic differentiation antigen gp100 has also been used as a vaccine and extended survival has been observed in the group of vaccinated patients. [10]

WT1 (Wilms Tumor protein 1) is an antigen expressed in a restricted set of normal cells including renal cells and hematopoietic cells. It is overexpressed in many leukemias. Vaccinations with WT1 antigenic peptide alone or with dendritic cells pulsed with the peptide have produced clinical responses in some patients. [11] [12]

For cervical carcinoma patients, long antigenic peptides derived from HPV proteins were used in cancer vaccines. It was shown that relative to the corresponding 9 amino acid peptides these peptides of 30-40 amino acids were better incorporated and presented by dendritic cells, leading to improved immunogenicity. Tumoral regressions were observed in initial stages of the disease. [13]

Adoptive cell transfer

Adoptive transfer involves either collecting from patients intratumoral or blood T cells, stimulate them in vitro against antigens present in the tumors and reinfuse them in large number into the patients, or using gene-modified T cells that recognize a tumor antigen.

Important tumor regressions were observed in patients treated with IL-2 and very large numbers (≥1010) of expanded TILs (tumor-infiltrating lymphocytes). [14] [15] Patients injected with expanded TILs directed against gp100 showed tumor regression but also significant adverse side effects such as uveitis. Adoptive transfer of TILs can increase the survival of melanoma patients when it is used as an adjuvant therapy, i.e. after a surgery and before the appearance of metastases. [16]

Complete remissions have been observed in leukemic patients infused with T cells genetically engineered to carry an artificial receptor that recognizes CD19, a differentiation antigen present at the surface of normal B lymphocytes and of B cell leukemias and lymphomas. [17]

Immunostimulatory antibodies

Immunostimulatory antibodies increase the activity of T lymphocytes through several mechanisms, including the blockade of inhibitory molecules that are present at the surface of T lymphocytes. These antibodies are often named "checkpoint inhibitors". Using them in cancer patients can lead to important and durable tumor regressions, and to improved survival of the patients. Clinical benefit from these treatments is positively correlated with the number of nonsynonymous mutations present in the tumors. This suggests that the clinical benefit depends on T lymphocytes that recognize tumor-specific antigens encoded by mutated genes [18] [19]

Related Research Articles

<span class="mw-page-title-main">Antigen</span> Molecule triggering an immune response (antibody production) in the host

In immunology, an antigen (Ag) is a molecule, moiety, foreign particulate matter, or an allergen, such as pollen, that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune response.

A cancer vaccine, or oncovaccine, is a vaccine that either treats existing cancer or prevents development of cancer. Vaccines that treat existing cancer are known as therapeutic cancer vaccines or tumor antigen vaccines. Some of the vaccines are "autologous", being prepared from samples taken from the patient, and are specific to that patient.

<span class="mw-page-title-main">Cancer immunotherapy</span> Artificial stimulation of the immune system to treat cancer

Cancer immunotherapy (immuno-oncotherapy) is the stimulation of the immune system to treat cancer, improving the immune system's natural ability to fight the disease. It is an application of the fundamental research of cancer immunology (immuno-oncology) and a growing subspecialty of oncology.

<span class="mw-page-title-main">Ipilimumab</span> Pharmaceutical drug

Ipilimumab, sold under the brand name Yervoy, is a monoclonal antibody medication that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

<span class="mw-page-title-main">Tumor antigen</span> Antigenic substance produced in tumor cells

Tumor antigen is an antigenic substance produced in tumor cells, i.e., it triggers an immune response in the host. Tumor antigens are useful tumor markers in identifying tumor cells with diagnostic tests and are potential candidates for use in cancer therapy. The field of cancer immunology studies such topics.

<span class="mw-page-title-main">MAGEA1</span> Mammalian protein found in humans

Melanoma-associated antigen 1 is a protein that in humans is encoded by the MAGEA1 gene.

<span class="mw-page-title-main">CTAG1B</span> Protein-coding gene in humans

Cancer/testis antigen 1 also known as LAGE2 or LAGE2B is a protein that in humans is encoded by the CTAG1B gene. It is most often referenced by its alias NY-ESO-1.

<span class="mw-page-title-main">PMEL (gene)</span> Protein-coding gene in humans

Melanocyte protein PMEL also known as premelanosome protein (PMEL), silver locus protein homolog (SILV) or Glycoprotein 100 (gp100), is a protein that in humans is encoded by the PMEL gene. Its gene product may be referred to as PMEL, silver, ME20, gp100 or Pmel17.

<span class="mw-page-title-main">MAGEA3</span> Protein-coding gene in humans

Melanoma-associated antigen 3 (MAGE-A3) is a protein that in humans is encoded by the MAGEA3 gene.

<span class="mw-page-title-main">MAGEA4</span> Protein-coding gene in humans

Melanoma-associated antigen 4 is a protein that in humans is encoded by the MAGEA4 gene.

<span class="mw-page-title-main">RAGE (gene)</span> Protein-coding gene in the species Homo sapiens

MAPK/MAK/MRK overlapping kinase is an enzyme that in humans is encoded by the RAGE gene.

<span class="mw-page-title-main">MLANA</span> Protein-coding gene in humans

Protein melan-A also known as melanoma antigen recognized by T cells 1 or MART-1 is a protein that in humans is encoded by the MLANA or "MALENA" gene. A fragment of the protein, usually consisting of the nine amino acids 27 to 35, is bound by MHC class I complexes which present it to T cells of the immune system. These complexes can be found on the surface of melanoma cells. Decameric peptides (26-35) are being investigated as cancer vaccines.

<span class="mw-page-title-main">CD200</span> Protein-coding gene in the species Homo sapiens

OX-2 membrane glycoprotein, also named CD200 is a human protein encoded by the CD200 gene. CD200 gene is in human located on chromosome 3 in proximity to genes encoding other B7 proteins CD80/CD86. In mice CD200 gene is on chromosome 16.

<span class="mw-page-title-main">MAGEA2</span> Protein-coding gene in humans

Melanoma-associated antigen 2 is a protein that in humans is encoded by the MAGEA2 gene.

Vaccine therapy is a type of treatment that uses a substance or group of substances to stimulate the immune system to destroy a tumor or infectious microorganisms such as bacteria or viruses.

Merkel cell polyomavirus was first described in January 2008 in Pittsburgh, Pennsylvania. It was the first example of a human viral pathogen discovered using unbiased metagenomic next-generation sequencing with a technique called digital transcriptome subtraction. MCV is one of seven currently known human oncoviruses. It is suspected to cause the majority of cases of Merkel cell carcinoma, a rare but aggressive form of skin cancer. Approximately 80% of Merkel cell carcinoma (MCC) tumors have been found to be infected with MCV. MCV appears to be a common—if not universal—infection of older children and adults. It is found in respiratory secretions, suggesting that it might be transmitted via a respiratory route. However, it has also been found elsewhere, such as in shedded healthy skin and gastrointestinal tract tissues, thus its precise mode of transmission remains unknown. In addition, recent studies suggest that this virus may latently infect the human sera and peripheral blood mononuclear cells.

Adoptive cell transfer (ACT) is the transfer of cells into a patient. The cells may have originated from the patient or from another individual. The cells are most commonly derived from the immune system with the goal of improving immune functionality and characteristics. In autologous cancer immunotherapy, T cells are extracted from the patient, genetically modified and cultured in vitro and returned to the same patient. Comparatively, allogeneic therapies involve cells isolated and expanded from a donor separate from the patient receiving the cells.

Gustav Gaudernack is a scientist working in the development of cancer vaccines and cancer immunotherapy. He has developed various strategies in immunological treatment of cancer. He is involved in several ongoing cellular and immuno-gene therapeutic clinical trials and his research group has put major efforts into the development of various T cell-based immunotherapeutic strategies.

Cancer/testis (CT) antigens are a group of proteins united by their importance in development and in cancer immunotherapy. In general, expression of these proteins is restricted to male germ cells in the adult animal. However, in cancer these developmental antigens are often re-expressed and can serve as a locus of immune activation. Thus, they are often classified as tumor antigens. The expression of CT antigens in various malignancies is heterogeneous and often correlates with tumor progression. CT antigens have been described in melanoma, liver cancer, lung cancer, bladder cancer, and pediatric tumors such as neuroblastoma. Gametogenesis offers an important role for many of these antigens in the differentiation, migration, and cell division of primordial germ cells, spermatogonia spermatocytes and spermatids. Because of their tumor-restricted expression and strong in vivo immunogenicity, CT antigens are identified as ideal targets for tumor specific immunotherapeutic approaches and prompted the development of several clinical trials of CT antigens-based vaccine therapy. CT antigens have been found to have at least 70 families so far, including about 140 members, most of which are expressed during spermatogenesis. Their expression are mainly regulated by epigenetic events, specifically, DNA methylation.

Individualized cancer immunotherapy, also referred to as individualized immuno-oncology, is a novel concept for therapeutic cancer vaccines that are truly personalized to a single individual.

References

  1. ↑ Boon T., Cerottini J.-C., Van den Eynde B., van der Bruggen P., Van Pel A. 1994. " Tumor antigens recognized by T lymphocytes ". Annual Review of Immunology. 12: 337-365.
  2. 1 2 Coulie P., Van den Eynde B.J., van der Bruggen P., Boon T. 2014. " Tumor antigens recognized by T lymphocytes: at the core of cancer immunotherapy ". Nature Reviews Cancer. 14(2): 135-146.
  3. ↑ Van den Eynde B., Lethé B., Van Pel A., De Plaen E., Boon T. 1991. " The gene coding for a major tumor rejection antigen of tumor P815 is identical to the normal gene of syngeneic DBA/2 mice ". The Journal of Experimental Medicine. 173: 1373-1384.
  4. ↑ van der Bruggen P., Traversari C., Chomez P., Lurquin C., De Plaen E., Van den Eynde B., Knuth A., Boon T. 1991. " A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma ". Science. 254(5038): 1643-1647.
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