Antigen spreading-induced CD8+T cells confer protection against the lethal
challenge of wild-type malignant mesothelioma by eliminating myeloid-derived
suppressor cells
#MMPMID26431275
Yu Z
; Tan Z
; Lee BK
; Tang J
; Wu X
; Cheung KW
; Lo NT
; Man K
; Liu L
; Chen Z
Oncotarget
2015[Oct]; 6
(32
): 32426-38
PMID26431275
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A key focus in cancer immunotherapy is to investigate the mechanism of
efficacious vaccine responses. Using HIV-1 GAG-p24 in a model PD1-based DNA
vaccine, we recently reported that vaccine-elicited CD8+ T cells conferred
complete prevention and therapeutic cure of AB1-GAG malignant mesothelioma in
immunocompetent BALB/c mice. Here, we further investigated the efficacy and
correlation of protection on the model vaccine-mediated antigen spreading against
wild-type AB1 (WT-AB1) mesothelioma. We found that this vaccine was able to
protect mice completely from three consecutive lethal challenges of AB1-GAG
mesothelioma. Through antigen spreading these animals also developed
tumor-specific cytotoxic CD8+ T cells, but neither CD4+ T cells nor antibodies,
rejecting WT-AB1 mesothelioma. A majority of these protected mice (90%) were also
completely protected against the lethal WT-AB1 challenge. Adoptive cell transfer
experiments further demonstrated that antigen spreading-induced CD8+ T cells
conferred efficacious therapeutic effects against established WT-AB1 mesothelioma
and prevented the increase of exhausted PD-1+ and Tim-3+ CD8+ T cells. A
significant inverse correlation was found between the frequency of functional
PD1-Tim3- CD8+ T cells and that of MDSCs or tumor mass in vivo. Mechanistically,
we found that WT-AB1 mesothelioma induced predominantly polymorphonuclear (PMN)
MDSCs in vivo. In co-cultures with efficacious CD8+ T cells, a significant number
of PMN-MDSCs underwent apoptosis in a dose-dependent way. Our findings indicate
that efficacious CD8+ T cells capable of eliminating both tumor cells and MDSCs
are likely necessary for fighting wild-type malignant mesothelioma.
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