Tumor Antigen-Induced T Cell Exhaustion

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Tumor Antigen-Induced T Cell Exhaustion: The Nemesis of Immune “Hot” Tumors

Tumor Antigen-Induced T Cell Exhaustion: The Nemesis of Immune “Hot” Tumors

Currently, immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis have achieved significant success in the clinical treatment of various cancer types.

However, many questions still remain unanswered regarding their mechanisms of action, biomarkers guiding therapy, factors determining sensitivity and resistance, and treatment combinations that enhance clinical responses.

Solid tumors develop within complex tumor microenvironments, and high levels of tumor-infiltrating lymphocytes (TILs) are often associated with favorable prognosis.

However, effector T (Teff) cells may be exposed to immune regulatory signals from the tumor microenvironment (TME) that can influence transcription and epigenetics due to continuous antigen stimulation.

This exposure can limit their activity and result in a functional impairment known as T cell exhaustion.

Teff cell functional impairment encompasses various T cell characteristics, including alterations in differentiation and cytolytic properties, disruptions in proliferation and apoptosis, and increased expression of various immune inhibitory signals such as PD-1, LAG-3, TIM-3, TIGIT, and CD39.

Recent research utilizing a single-cell approach has explored the functional characteristics and clinical significance of tumor antigen-specific effector T cells in human melanoma and lung cancer.

These findings expand our understanding of T cell alterations in the tumor microenvironment and demonstrate that CD8+ T cell exhaustion is mediated by exposure to tumor cell-specific antigens and is associated with a tissue-resident memory phenotype.

Tumor Antigen-Induced T Cell Exhaustion: The Nemesis of Immune "Hot" Tumors

A study evaluated the single-cell transcriptomes, T cell receptor (TCR) repertoires, and selected surface proteins of tumor antigen-specific CD8+ Teff TILs in four melanoma patients who underwent surgical resection. Based on the distribution of dominant Teff clones, they were ultimately categorized into two functional categories: exhausted cells and non-exhausted memory cells.

The most expanded TCR clones of CD8+ Teff cells primarily exhibited exhaustion features and expressed transcripts associated with tissue-resident memory (TRM) cells, such as ITGAE (encoding CD103) and ZNF683.

Furthermore, when T cells from non-cancer individuals were introduced, the majority (83%) of TCR clones from exhausted CD8+ Teff cells exhibited autoreactivity against cancer cells, whereas only 10% of TCRs from non-exhausted cells showed reactivity. Most TCRs isolated from TILs recognized one or more tumor-specific antigens with common HLA restrictions. In a study of 14 melanoma patients, exhausted tumor antigen-specific CD8+ Teff cells were rare in initial peripheral blood samples but became detectable in patients who progressed after ICI therapy. These exhausted cells were characterized by high levels of PD-1 and CD39 expression.

In summary, these results indicate that tumor antigen-specific Teff cells exhibit exhaustion features, a state acquired through continuous exposure to tumor antigen stimulation. These findings align with previous research indicating a close association between tumor antigen-specific Teff cell exhaustion and other malignant tumor patient TILs. While these studies also report a high abundance of non-exhausted virus-specific bystander T cells, it appears they do not significantly contribute to anti-tumor responses.

Another study analyzed the single-cell transcriptomic characteristics and TCR sequences of ex vivo expanded tumor antigen-specific CD8+ Teff cells from 20 non-small cell lung cancer patients treated with nivolumab neoadjuvant therapy. Based on transcriptomic analysis, 15 T cell clusters were identified, with six showing expression patterns consistent with TRM cells.

Most new antigen-specific CD8+ Teff cell clones were allocated to different TRM cell clusters, characterized by incomplete effector functionality, increased immune inhibitory signals, upregulated TRM markers, and increased expression of transcription factors associated with T cell exhaustion (PRDM1 and TOX2). These features were not observed in virus-specific bystander T cells.

In conclusion, these studies collectively suggest that tumor antigen-specific cells exhibit a TRM phenotype and display features of exhaustion or functional impairment. Additionally, compared to virus-specific T cells, new antigen-specific CD8+ Teff cells exhibit reduced expression of IL-7R and sensitivity to IL-7 stimulation.

These studies expand our understanding of T cell alterations in immune “hot” tumors and conclusively demonstrate that CD8+ Teff cell exhaustion is mediated by exposure to tumor cell antigens and is significantly associated with the TRM phenotype.

These studies also demonstrate the presence of non-exhausted bystander cells at various levels, which may lead to pseudo-immune “hot” tumors and reduce sensitivity to ICI therapy.

Potential therapeutic options to reduce or control the negative impact of T cell functional impairment in the TME include using combination therapies targeting multiple common inhibitory signals or receptors, adopting adoptive cell therapy with genetically modified (e.g., anti-exhaustion) tumor antigen-specific T cells, or modulating the IL-7 pathway.

Further research is needed to confirm the clinical significance of these findings, expand our understanding of the role of TRM cells in ICI responses, and uncover the specific molecular mechanisms of tumor antigen-specific T cell functional impairment.