The decreased susceptibility of metastatic melanoma cells to killing involves an alteration of CTL reactivity.
Metastases are known to be more resistant to therapy than matching primary tumors, in particular they are less prone to apoptosis. In this study we investigated the functional interaction of a CTL clone (LT12) specific for a melanoma TA with the primary tumor (T1) versus its metastatic counterpart (G1). The CTL clone (LT12) was shown to lyse the primary T1 cells more efficiently in a classical cytotoxicity test. This differential susceptibility was not associated with MHC class I down-regulation and conjugate formation but correlated with a differential increase in Ca++ flux in the LT12 CTL when stimulated with the primary versus the metastatic tumor cells. Since LT12 uses perforin/granzyme B to kill its autologous target we analysed perforin and granzyme B mRNA expression in the CTL in the presence of either primary and metastatic melanoma cells. Quantitative PCR analysis showed an increased expression of granzyme B and perforin mRNA levels in LT12 when cocultured in the presence of the primary tumor. However, a similar level of (cytotoxic molecule) degranulation as revealed by CD107 expression was observed when LT12 was stimulated with T1 or G1 cells. These data suggest that the differential susceptibility of primary and metastatic melanoma cells involves at least in part their distinct potential to induce autologous CTL reactivity and the subsequent triggering of granzyme B and perforin in these cells.
Gassara
Ahmed
A
Unit 753 INSERM, Institut Gustave Roussy, 94805 Villejuif, France.
Messai
Yosra
Y
Gaudin
Catherine
C
Abouzahr
Soraya
S
Jalil
Adbelali
A
Diarra-Mehrpour
Maryam
M
Faure
Florence
F
Richon
Catherine
C
Avril
Marie-Françoise
MF
Even
Jos
J
Chouaib
Salem
S
D000368:Aged; D002118:Calcium / Q000378:metabolism; D002450:Cell Communication; D015550:Cell Degranulation / Q000276:immunology; D045744:Cell Line, Tumor; D002999:Clone Cells; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D015536:Down-Regulation; D053804:Granzymes / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008545:Melanoma / Q000276:immunology* / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009362:Neoplasm Metastasis; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012878:Skin Neoplasms / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism
D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D054353:Perforin; D053804:Granzymes; D002118:Calcium