Lack of terminally differentiated tumor-specific CD8+ T cells at tumor site in spite of antitumor immunity to self-antigens in human metastatic melanoma.
Activation of CTL-mediated antitumor immunity to self-epitopes expressed by neoplastic cells is thought to be prevented, at any stage of tumor progression, by tolerance mechanisms. In contrast, in 74 American Joint Committee on Cancer stages I-IV melanoma patients, we found that development of lymph node metastases is a key event triggering CD8(+) T-cell-mediated immunity to self-epitopes encoded by melanocyte differentiation antigens. This was shown by the increased peripheral precursor frequency to Melan-A/Mart-1, gp100, and tyrosinase epitopes in stage III and IV compared with stage I and II patients, and by accumulation of functional memory T cells directed to Melan-A/Mart-1(26-35) in tumor-invaded lymph nodes. However, in tumor-invaded lymph nodes of most patients, CD8(+) T cells directed to melanocyte differentiation antigens or to tumor-restricted antigens (MAGE-3 and NY-ESO-1 epitopes), showed a CCR7(+) CD45RA(+) CD27(+) CD28(+) perforin(-) "precursor" phenotype. Only in 7 of 23 cases antigen-specific CD8(+) T cells in invaded lymph nodes showed a predominant CCR7(-) CD45RA(-) CD27(+) CD28(-) perforin(+) "preterminally differentiated" phenotype. In the latter subset of patients, by immunohistochemistry in lymph node lesions, we found that CD8(+) T lymphocytes intermingling with the neoplastic tissue expressed a CCR7(-) CD45RO(+)/RA(-) phenotype, whereas CD4(+) lymphocytes did not infiltrate the tumor. Furthermore, perforin and granzyme B were expressed on a higher fraction of the CD8(+) cells surrounding the invading tumor compared with the lymphocytes infiltrating the neoplastic tissue. In addition, no evidence for tumor regression was found in such metastatic lesions, as documented by absence of neoplastic cell necrosis or apoptosis. These data indicate that neoplastic cells in the lymph nodes and/or increased tumor burden in metastatic disease activate CD8(+) T-cell-mediated antitumor immunity to self-epitopes. However, the paucity of terminally differentiated CD8(+) T cells at tumor site suggests that immunotherapy strategies may require not only the boosting of tumor immunity, but also effective means to promote CD8(+) T-cell differentiation in the neoplastic tissue.
Mortarini
Roberta
R
Human Tumors Immunobiology, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milan, 20133, Italy.
Piris
Adriano
A
Maurichi
Andrea
A
Molla
Alessandra
A
Bersani
Ilaria
I
Bono
Aldo
A
Bartoli
Cesare
C
Santinami
Mario
M
Lombardo
Claudia
C
Ravagnani
Fernando
F
Cascinelli
Natale
N
Parmiani
Giorgio
G
Anichini
Andrea
A
D000951:Antigens, Neoplasm / Q000276:immunology; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002454:Cell Differentiation / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D053804:Granzymes; D015234:HLA-A Antigens / Q000276:immunology; D015789:HLA-A2 Antigen; D006801:Humans; D007156:Immunologic Memory; D017493:Leukocyte Common Antigens / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D058965:MART-1 Antigen; D008545:Melanoma / Q000276:immunology* / Q000473:pathology / Q000556:secondary; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology; D008565:Membrane Proteins; D014442:Monophenol Monooxygenase / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology; D009367:Neoplasm Staging; D010446:Peptide Fragments / Q000276:immunology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins / Q000276:immunology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000276:immunology; D012697:Serine Endopeptidases / Q000096:biosynthesis; D058951:gp100 Melanoma Antigen
D000951:Antigens, Neoplasm; D001324:Autoantigens; C515370:CCR7 protein, human; C104948:CTAG1B protein, human; D018984:Epitopes, T-Lymphocyte; D015234:HLA-A Antigens; C435939:HLA-A*02:01 antigen; D015789:HLA-A2 Antigen; C072013:MAGEA3 protein, human; D058965:MART-1 Antigen; C548667:MLANA protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009363:Neoplasm Proteins; C548637:PMEL protein, human; D010446:Peptide Fragments; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D058951:gp100 Melanoma Antigen; D054353:Perforin; D014442:Monophenol Monooxygenase; D017493:Leukocyte Common Antigens; C509213:GZMB protein, human; D053804:Granzymes; D012697:Serine Endopeptidases