T Cell Antigens in Cancer Immunotherapy: A Comprehensive Overview

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T Cell Antigens in Cancer Immunotherapy: A Comprehensive Overview

T Cell Antigens in Cancer Immunotherapy: A Comprehensive Overview

In recent years, significant breakthroughs have been achieved in cancer immunotherapy, bringing substantial clinical benefits.

While various immunotherapy approaches exist, a considerable focus has been placed on cytotoxic T lymphocytes (CTLs) targeting tumor cells.

T Cell Antigens in Cancer Immunotherapy: A Comprehensive Overview

T cells are activated through the interaction of the T cell receptor (TCR) with antigens. V(D)J recombination in the thymus generates a vast diversity of T cell clones, theoretically up to 10^15, each with a unique TCR. Through further selection processes, approximately 10^6-10^10 circulating T cell clones are eventually produced.

T cell antigens are presented on two major histocompatibility complex (MHC) molecules known as human leukocyte antigens (HLAs).

MHC class I molecules are expressed by all nucleated cells, while MHC class II molecules are expressed by antigen-presenting cells (APCs), epithelial cells, and some tumor cells.

The peptides on MHC class I are recognized by CD8+ CTLs, while those on MHC class II are recognized by CD4+ T cells. Cross-presentation of T cell antigens, crucial for CD8+ T cell activation and tumor recognition, involves specific dendritic cell types.

T Cell Antigens in Cancer Immunotherapy: A Comprehensive Overview

Currently, cancer immunorejection responses are thought to be T cell-mediated, with anti-tumor T cell responses being antigen-specific.

Advances in immunotherapy and available methods for T cell antigen identification have sparked interest in recognizing and characterizing T cell antigens presented by tumors, extending beyond classical tumor-specific antigens (TSAs) and tumor-associated antigens (TAAs) to previously less explored sources such as non-standard proteins and bacterial proteins.

Self Antigens:
- Tumor-associated self-antigens exhibit differential expression patterns in tumors without mutations. Examples include MART-1, gp100, and tyrosinase, expressed in melanoma. Tebentafusp, a soluble fusion protein targeting gp100-specific TCR and anti-CD3, has demonstrated clinical benefits in uveal melanoma patients, receiving FDA approval. However, tissue-specific antigens face limitations due to potential damage to surrounding healthy tissues.
- Cancer germline antigens, originating from proteins expressed only in reproductive tissues, represent another class of self-antigens. Analyzing 153 cancer germline genes revealed their highest aberrant expression in skin, lung, liver, and brain cancers. Their unique expression patterns and high prevalence make them intriguing immunotherapy targets.
Neoantigens Derived from Genomic Alterations:
- Features of mutation-derived neoantigens include cancer-related sequence alterations from somatic point mutations, frameshifts, or chromosomal aberrations. Non-synonymous mutations can produce true TSAs, potentially leading to HLA-binding novel peptides. The presence of insertions/deletions and translocations is associated with a significant response to anti-PD-1 or anti-CTLA-4 therapies.
- Fusion genes, like BCR–ABL in leukemia and EML4–ALK in non-small cell lung cancer (NSCLC), generate T cell-recognizable neoantigens.
Tumor Antigens from Non-Conventional Transcription and Post-Transcriptional Alterations:
- Growing evidence suggests frequent non-coding gene translation in tumors, leading to immune responses against tumor antigens from non-coding regions. Various non-coding elements contribute to shared and tumor-specific non-canonical HLA-presented peptides.
- Examples of antigen-specific T cell responses to intronic sequences include N-acetylglucosaminyltransferase V gene intron, incomplete splice variants of gp100, and 5’UTR region of c-akt oncogene.
- Translation reprogramming and compromised translation fidelity in cancer cells may produce non-standard translated peptides, potentially serving as new immunogenic antigens.
Pathogen-Derived Tumor-Associated Antigens:
- Tumor-associated antigens derived from pathogens are remnants of bacterial or viral infections. Pathogens like Helicobacter pylori, human papillomavirus (HPV), and hepatitis B and C viruses (HBV and HCV) can persist in host cells, mediating malignant transformation.
- Specific T cell responses against pathogen-derived antigens have shown promise in eliciting immune responses against cancer cells.
- Emerging evidence suggests the possibility of fungal-derived antigens as another source of tumor antigens.
Characteristics Facilitating Anti-Tumor Immunity:
- The effectiveness of any given antigen in anti-tumor immunity depends on a combination of properties. Some, like immunogenicity and effective cross-presentation, are unique to T cell targets, while others, such as population-wide prevalence, disease specificity, clonality, and functional significance, apply to any form of targeted therapy.
- Optimal combinations of these features are crucial for determining the efficacy of a given antigen. For instance, mutation-derived neoantigens exhibit high immunogenicity but are often personalized, whereas self-antigens are broadly applicable but with lower immunogenicity.

In conclusion, understanding the diverse landscape of T cell antigens in cancer immunotherapy is vital for developing effective and targeted treatments.

The exploration of various antigen categories, from self-antigens to neoantigens and beyond, provides a comprehensive perspective on the potential targets for advancing anti-cancer immune responses.

Ongoing research in this field continues to unravel new possibilities and refine strategies for personalized and effective cancer immunotherapies.