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Single-cell Profiles and Prognostic Impact of Tumor-Infiltrating Lymphocytes Coexpressing CD39, CD103, and PD-1 in Ovarian Cancer
- Source :
- Clinical Cancer Research. 27:4089-4100
- Publication Year :
- 2021
- Publisher :
- American Association for Cancer Research (AACR), 2021.
-
Abstract
- Purpose: Tumor-infiltrating lymphocytes (TIL) are strongly associated with survival in most cancers; however, the tumor-reactive subset that drives this prognostic effect remains poorly defined. CD39, CD103, and PD-1 have been independently proposed as markers of tumor-reactive CD8+ TIL in various cancers. We evaluated the phenotype, clonality, and prognostic significance of TIL expressing various combinations of these markers in high-grade serous ovarian cancer (HGSC), a malignancy in need of more effective immunotherapeutic approaches. Experimental Design: Expression of CD39, CD103, PD-1, and other immune markers was assessed by high-dimensional flow cytometry, single-cell sequencing, and multiplex immunofluorescence of primary and matched pre/post-chemotherapy HGSC specimens. Results: Coexpression of CD39, CD103, and PD-1 (“triple-positive” phenotype) demarcated subsets of CD8+ TIL and CD4+ regulatory T cells (Treg) with a highly activated/exhausted phenotype. Triple-positive CD8+ TIL exhibited reduced T-cell receptor (TCR) diversity and expressed genes involved in both cytolytic and humoral immunity. Triple-positive Tregs exhibited higher TCR diversity and a tumor-resident phenotype. Triple-positive TIL showed superior prognostic impact relative to TIL expressing other combinations of these markers. TIGIT was uniquely upregulated on triple-positive CD8+ effector cells relative to their CD4+ Treg counterparts. Conclusions: Coexpression of CD39, CD103, and PD-1 demarcates highly activated CD8+ and CD4+ TIL with inferred roles in cytolytic, humoral, and regulatory immune functions. Triple-positive TIL demonstrate exceptional prognostic significance and express compelling targets for combination immunotherapy, including PD-1, CD39, and TIGIT.
- Subjects :
- Cancer Research
Programmed Cell Death 1 Receptor
chemical and pharmacologic phenomena
Biology
Flow cytometry
Lymphocytes, Tumor-Infiltrating
Immune system
TIGIT
Antigens, CD
medicine
Humans
Ovarian Neoplasms
medicine.diagnostic_test
Tumor-infiltrating lymphocytes
Apyrase
T-cell receptor
hemic and immune systems
Prognosis
medicine.disease
Phenotype
Cystadenocarcinoma, Serous
Oncology
Cancer research
Female
Ovarian cancer
Integrin alpha Chains
CD8
Subjects
Details
- ISSN :
- 15573265 and 10780432
- Volume :
- 27
- Database :
- OpenAIRE
- Journal :
- Clinical Cancer Research
- Accession number :
- edsair.doi.dedup.....6e93a77082ce25480273f9ea0ba7c718