Non-redundant role for IL-12 and IL-27 in modulating Th2 polarization of carcinoembryonic antigen specific CD4 T cells from pancreatic cancer patients.
BACKGROUND
Pancreatic cancer is a very aggressive disease with dismal prognosis; peculiar is the tumor microenvironment characterized by an extensive fibrotic stroma, which favors rapid tumor progression. We previously reported that pancreatic cancer patients have a selective Th2 skew in the anti-carcinoembryonic antigen (CEA) CD4(+) T cell immunity, which correlates with the presence of a predominant GATA-3(+) tumor lymphoid infiltrate. This has negative effects in both effective anti-tumor immunity and further favoring fibrinogenesis. Aim of this study was to evaluate whether the Th2 polarization of CEA-specific CD4(+) T cells from pancreatic cancer patients is stable or can be reverted by immunomodulating cytokines.


RESULTS
We first evaluated the influence of IL-12 and IL-27, as single agents and in association, on the polarization of CEA-specific Th2 CD4(+) T cell clones from a pancreatic cancer patient. We found that only the combination of IL-12 and IL-27 modified the polarization of Th2 effectors by both reduction of IL-5, GM-CSF and IL-13 and induction of IFN-gamma production, which lasted after cytokine removal. Second, we evaluated the effect of the combined treatment on polyclonal CEA-specific CD4(+) T cells in short-time re-stimulation assays. In agreement with the data obtained with the clones, we found that the combined treatment functionally modulated the Th2 polarization of CEA-specific CD4(+) T cells and enhanced pre-existing Th1 type immunity.


CONCLUSIONS
Collectively, our results demonstrate that tumor antigen specific Th2 CD4(+) T cells in pancreatic cancer are endowed with functional plasticity. Hence, loco-regional cytokines delivery or targeted therapy based on antibodies or molecules directed to the tumor stroma might improve anti-tumor immunity and ameliorate fibrosis, without systemic toxicity.
Tumor Immunology Unit, San Raffaele Scientific Institute, Milan, Italy.
Elena
E
Tassi
Marco
M
Braga
Renato
R
Longhi
Francesca
F
Gavazzi
Giorgio
G
Parmiani
Valerio
V
Di Carlo
Maria Pia
MP
Protti
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D002272:Carcinoembryonic Antigen / Q000378:metabolism*; D015331:Cohort Studies; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005355:Fibrosis; D005434:Flow Cytometry / Q000379:methods; D050990:GATA3 Transcription Factor / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D018664:Interleukin-12 / Q000502:physiology*; D007378:Interleukins / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000097:blood* / Q000378:metabolism*; D018418:Th2 Cells / Q000166:cytology*
D002272:Carcinoembryonic Antigen; D016207:Cytokines; D050990:GATA3 Transcription Factor; D007378:Interleukins; C464565:MYDGF protein, human; D018664:Interleukin-12; D007371:Interferon-gamma