Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired.
Tumor antigen-specific T cells are found within melanomas, yet tumors continue to grow. Although the tumor microenvironment is thought to influence the suppression of tumor-reactive T cells, the underlying mechanisms for this T-cell dysfunction are not clear. Here, we report that the majority of tumor infiltrating T lymphocytes (TIL), including MART-1/Melan-A melanoma antigen-specific CD8 T cells, predominantly expressed PD-1, in contrast to T cells in normal tissues and peripheral blood T lymphocytes (PBL). PD-1(+) TIL expressed CTLA-4 and Ki-67, markers that were not expressed by PD-1(-) TIL and T cells in the normal tissues and PBL. Moreover, PD-1(+) TIL were primarily HLA-DR(+) and CD127(-), in contrast to PD-1(-) TIL. Effector cytokine production by PD-1(+) TIL was impaired compared with PD-1(-) TIL and PBL. Collectively, the phenotypic and functional characterizations of TIL revealed a significantly higher frequency and level of PD-1 expression on TIL compared with normal tissue T-cell infiltrates and PBL, and PD-1 expression correlated with an exhausted phenotype and impaired effector function. These findings suggest that the tumor microenvironment can lead to up-regulation of PD-1 on tumor-reactive T cells and contribute to impaired antitumor immune responses.
Surgery Branch, National Cancer Institute, NIH, Bethesda, MD 20892, USA. mojgan_ahmadzadeh@nih.gov
Mojgan
M
Ahmadzadeh
Laura A
LA
Johnson
Bianca
B
Heemskerk
John R
JR
Wunderlich
Mark E
ME
Dudley
Donald E
DE
White
Steven A
SA
Rosenberg
D000293:Adolescent; D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism*; D000951:Antigens, Neoplasm / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000502:physiology*; D002648:Child; D003602:Cytotoxicity, Immunologic / Q000502:physiology; D005260:Female; D006801:Humans; D008213:Lymphocyte Activation / Q000502:physiology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism* / Q000473:pathology / Q000502:physiology*; D058965:MART-1 Antigen; D008297:Male; D008545:Melanoma / Q000097:blood / Q000276:immunology* / Q000378:metabolism / Q000503:physiopathology; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor; D019139:Tumor Escape / Q000276:immunology; D015854:Up-Regulation; D055815:Young Adult
D015703:Antigens, CD; D000951:Antigens, Neoplasm; D051017:Apoptosis Regulatory Proteins; D058965:MART-1 Antigen; C548667:MLANA protein, human; D009363:Neoplasm Proteins; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor