To investigate the association between the potentially functional polymorphisms in IL12A and IL12B, HBV infection and risk of hepatocellular carcinoma in a Chinese population, we genotyped three polymorphisms, rs568408 (3 0 UTR G>A), rs2243115(5 0 UTR T>G) in IL12A and rs3212227 (3 0 UTR A>C) in IL12B in a case-control study of 869 hepatocellular carcinoma (HCC)cases and 891 cancer-free controls. We found that the IL12A rs568408 GA/AA variant genotypes were associated with a significantly increased risk of HCC (adjusted odds ratio (OR) 5 1.53, 95% confidence interval (CI) 5 1.17-2.00), compared with the wild-type GG homozygote. In the stratified analyses, the increased risk of HCC associated with rs568408 GA/AA was more evident in patients who were negative for HBsAg (adjusted OR 5 1.71, 95% CI 5 1.23-2.39). However, no significant associations between IL12A rs2243115 T/G, IL12B rs3212227 A/C and risk of HCC were observed. Our findings indicate that IL12A rs568408 may contribute to the risk of HCC and modify HCC risk associated with HBV infection.

Objectives While myeloid-derived suppressor cells (MDSCs) were previously shown to promote a proinflammatory T helper (Th) 17 response in autoimmune conditions, a potential impact of the MDSC-Th17 immune axis on abnormal bone destruction in RA remains largely unknown. Methods We investigated the correlation between the frequency of MDSCs or its subsets and joint destruction in RA patients. The reciprocal actions of patient-derived MDSCs and Th17 cells were studied using osteoclast (OC) differentiation and bone resorption assays in vitro, which were further validated using mouse models of RA. Contribution of MDSCs to osteoclastogenesis and bone erosion in vivo was determined by depletion or transfer of MDSCs. Results Human MDSCs, particularly monocytic MDSCs (M-MDSCs), exhibit inherent OC-differentiating capacity and positively correlate with clinical bone erosion in RA patients. Strikingly, patient-derived M-MDSCs can program Th17 cells towards a pro-osteoclastogenic phenotype, which in return potentiates OC differentiation via the receptor activator of nuclear factor κΒ ligand (RANK-L)-RANK signalling. This enhanced osteolysis driven by the reciprocal actions of M-MDSCs and Th17 cells is further confirmed using mouse models of RA. Selective depletion of M-MDSCs significantly ameliorates osteoclastogenesis and disease severity in arthritic mice, whereas transfer of M-MDSCs aggravates bone erosion associated with increased OCs in recipient mice. Conclusion Our findings highlight the functional plasticity of MDSCs and identify a novel pro-osteoclastogenic pathway governed by interplay between myeloid cells and T lymphocytes in autoimmune RA.

<p>Supplementary Figure S7. MDA-7 modification promotes T cell proliferation in vivo.</p>

<p>Supplementary Figure S5. Alterations of tumor immune environment by MDA-7-producing T cells.</p>

<p>Supplementary Figure S6. Effects of MDA-7 engineering on phenotype, activation, and expansion of T cells.</p>

<p>Supplementary Figure S2. Schematic depiction of construction of human MDA-7/IL-24-encoding lentivirus (LV-MDA-7) and engineering of T cells.</p>

<p>Supplementary Figure S4. MDA-7/IL-24 engineering confers T cells with improved therapeutic activity in eradication of prostate cancer.</p>

<p>Supplementary Figure S1. Characterization of tumor-sensitized T cells expanded with y-chain cytokines.</p>