BACKGROUND The objectives of this study were to determine 1) expression of oral secretory leukocyte protease inhibitor (SLPI) in HIV-infected subjects compared to non-HIV controls, 2) the oral SLPI expression in HIV-infected subjects with ART compared to those without ART, and 3) factors associated with the expression of oral SLPI. METHODS Oral tissues and samples of both un-stimulated and stimulated saliva were collected from HIV-infected subjects with and without ART, and non-HIV individuals. The expression of SLPI mRNA in the tissue was determined by quantitative real-time PCR. Salivary SLPI protein was detected using ELISA. Chi-square test and logistic regression analysis were performed to determine the association between HIV/ART status and the expression of oral SLPI. RESULTS One hundred and fifty-seven HIV-infected subjects were enrolled; 99 on ART (age range 23–57 yr, mean 39 yr), 58 not on ART (age range 20–59 yr, mean 34 yr), and 50 non-HIV controls (age range 19–59 yr, mean 36 yr). The most common ART regimen was 2 NRTIs+1 NNRTI. The expression of oral SLPI in stimulated saliva was significantly decreased with HIV infection (p< 0.001). The expression was also significantly different with respect to ART use (p=0.007). Smoking, CD4+ cell count, and HIV viral load were the factors associated with the oral SLPI expression. CONCLUSION The expression of oral SLPI is altered by HIV infection and use of ART. Thus, oral SLPI may be the useful biomarker to identify subjects at risk of infections and malignant transformation due to HIV infection and long-term ART.

Signals from the tumor microenvironment (TME) have a profound influence on the maintenance and progression of cancers. Chronic inflammation and the infiltration of immune cells in breast cancer (BC) have been strongly associated with early carcinogenic events and a switch to a more immunosuppressive response. Cancer-associated fibroblasts (CAFs) are the most abundant stromal component and can modulate tumor progression according to their secretomes. The immune cells including tumor-infiltrating lymphocytes (TILs) (cytotoxic T cells (CTLs), regulatory T cells (Tregs), and helper T cell (Th)), monocyte-infiltrating cells (MICs), myeloid-derived suppressor cells (MDSCs), mast cells (MCs), and natural killer cells (NKs) play an important part in the immunological balance, fluctuating TME between protumoral and antitumoral responses. In this review article, we have summarized the impact of these immunological players together with CAF secreted substances in driving BC progression. We explain the crosstalk of CAFs and tumor-infiltrating immune cells suppressing antitumor response in BC, proposing these cellular entities as predictive markers of poor prognosis. CAF-tumor-infiltrating immune cell interaction is suggested as an alternative therapeutic strategy to regulate the immunosuppressive microenvironment in BC.

Background Carcinoma-associated fibroblasts (CAFs) play a critical role in cancer progression and immune cell modulation. In this study, it was aimed to evaluate the roles of CAFs-derived IL-6 in doxorubicin (Dox) resistance and PD-L1-mediated chimeric antigenic receptor (CAR)-T cell resistance in breast cancer (BCA). Methods CAF conditioned-media (CM) were collected, and the IL-6 level was measured by ELISA. CAF-CM were treated in MDA-MB-231 and HCC70 TNBC cell lines and siIL-6 receptor (IL-6R) knocked down (KD) cells to determine the effect of CAF-derived IL-6 on Dox resistance by flow cytometry and on increased PD-L1 through STAT3, AKT and ERK1/2 pathways by Western blot analysis. After pre-treating with CM, the folate receptor alpha (FRα)-CAR T cell cytotoxicity was evaluated in 2D and 3D spheroid culture assays. Results The results showed a significant level of IL-6 in CAF-CM compared to that of normal fibroblasts (NFs). The CM with high IL-6 level significantly induced Dox resistance; and PD-L1 expression through STAT3 and AKT pathways in MDA-MB-231 and HCC70 cells. These induction effects were attenuated in siIL-6R KD cells. Moreover, the TNBC cell lines that were CM-treated with STAT3 and an AKT inhibitor had a reduced effect of IL-6 on PD-L1 expression. BCA cells with high IL-6 containing-CM treatment had resistance to cancer cell killing by FRα CAR-T cells compared to untreated cells. Conclusion These results highlight CAF-derived IL-6 in the resistance of chemotherapy and T cell therapy. Using inhibitors of IL6-STAT3/AKT-PD-L1 axis may provide a potential benefit of Dox and CAR-T cell therapies in BCA patients.

Mutation screening of the NRXN1gene in patients with ID and ASD may be useful to identify potential variants predisposing to ID and ASD. However, further studies utilizing protein functional analysis of the novel variants are required for a more definite conclusion.