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Human prostate-infiltrating CD8+ T lymphocytes are oligoclonal and PD-1+
Karen S Sfanos1, Tullia C Bruno, Alan K Meeker
1Department of Pathology, Johns Hopkins Sidney Kimmel Comprehensive Cancer Center, Baltimore, Maryland 21231, USA.
Insights
Prostate cancer-infiltrating CD8(+) T cells show clonal expansion but are likely exhausted due to PD-1 expression. This suggests potential for PD-1 blockade immunotherapy in prostate cancer treatment.
Area of Science:
- Immunology
- Oncology
- T-cell biology
Background:
- Prostate cancer (PCa) frequently features CD8(+) T lymphocytes (CD8(+) PIL).
- It remains uncertain if these cells represent a non-specific infiltrate or an antigen-driven adaptive response.
Purpose of the Study:
- To investigate the T-cell receptor (TCR) repertoire complexity of CD8(+) PIL in PCa.
- To analyze the expression of programmed cell death 1 (PD-1) on these T cells.
Main Methods:
- Examined TCR Vbeta gene sequences in prostate and peripheral blood CD8(+) T cells.
- Utilized Vbeta spectratyping, flow cytometry, and direct sequencing.
- Assessed PD-1 expression on CD8(+) T cells and CD8(+) PIL.
Main Results:
- CD8(+) PIL demonstrated restricted TCR Vbeta gene usage, indicating clonal expansion.
- Identical T-cell clones were found in multiple prostate locations.
- High PD-1 expression was observed on CD8(+) PIL, suggesting T-cell exhaustion.
Conclusions:
- CD8(+) PIL likely underwent clonal expansion against an unknown antigen.
- High PD-1 levels may impair the anti-tumor immune response.
- Identifying prostatic antigens and exploring PD-1 blockade could be beneficial for PCa immunotherapy.
Background:
Prostate-infiltrating CD8(+) T lymphocytes (CD8(+) PIL) are prevalent in men with prostate cancer (PCa), however, it is unclear whether the presence of such cells reflects a non-specific immune infiltrate or an oligoclonal, antigen-driven adaptive immune response.
Methods:
We investigated the complexity of the T-cell receptor (TCR) repertoire in the prostate gland by examining the diversity of CD8(+) TCR beta chain variable region (Vbeta) gene sequences in both the peripheral blood and prostates of cancer patients. Vbeta repertoire analysis was performed by family-specific Vbeta spectratyping and flow cytometry, as well as direct sequence analysis (5' RACE and cloning). Programmed cell death 1 (PD-1 or PDCD1) expression on peripheral blood CD8(+) T cells and CD8(+) PIL was analyzed by flow cytometry.
Results:
CD8(+) PIL isolated from cancer patients exhibited restricted TCR Vbeta gene usage, and identical clones were identified in multiple sites within the prostate. Furthermore, CD8(+) PIL express high levels of the inhibitory receptor PD-1, a cell surface protein associated with an "exhausted" CD8(+) T-cell phenotype.
Conclusions:
CD8(+) PIL appear to have undergone clonal expansion in response to an as yet unidentified antigen; however, due to the high expression of PD-1, these cells are likely incapable of mounting an effective immune response. The results provide an important basis for further efforts aimed at the identification of specific antigens involved in prostatic inflammation, and suggest that PD-1 blockade may be useful in immunotherapy for PCa.
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