Foxp3 Expression in CD4＋CD25＋Foxp3＋ Regulatory T Cells Promotes Development of Colorectal Cancer by Inhibiting Tumor Immunity

The mechanism underlying CD4~＋CD25~＋Foxp3~＋ regulatory T cells（Tregs） promoting the development of colorectal cancer（CRC） was elucidated in the present study. Forty-eight cases of colorectal carcinomas, 22 cases of colon polyps and 21 cases of normal colorectal tissues were collected. The correlation among Foxp3, IL-10 and Stat3, and the clinical relevance of these three indexes were analyzed. The results showed that the levels of Foxp3 expressed in infiltrating CD4~＋CD25~＋Foxp3~＋Tregs, and IL-10 and Stat3 in CRC tissues were all significantly higher than those in polypus tissues and normal colon tissues（P〈0.01）. Pearson correlation analysis indicated that the expression level of Foxp3 was positively correlated with Stat3 at m RNA level（r=0.526, P=0.036）, and was positively correlated with IL-10 at protein level（r=0.314, P=0.030）. The Foxp3 expressed in CD4~＋CD25~＋Foxp3~＋Tregs was correlated with the histological grade, lymph node metastasis and TNM stage of CRC（P〈0.05 for all）. The IL-10 expression was correlated with the histological grade and TNM stage（both P〈0.05）. The Stat3 expression was correlated with the lymph node metastasis and TNM stage（both P〈0.05）. It was concluded that CD4~＋CD25~＋Foxp3~＋Tregs can inhibit tumor immunity in combination with some other related inhibitory cytokines and that Foxp3 expression in CD4~＋CD25~＋Foxp3~＋Tregs correlates with CRC progression.

Biomimetic“Gemini nanoimmunoregulators”orchestrated for boosted photoimmunotherapy by spatiotemporally modulating PD-L1 and tumor-associated macrophages

A novel strategy of not only stimulating the immune cycle but also modulating the immunosuppressive tumor microenvironment is of vital importance to efficient cancer immunotherapy.Here,a new type of spatiotemporal biomimetic“Gemini nanoimmunoregulators”was engineered to activate robust systemic photoimmunotherapy by integrating the triple-punch of amplified immunogenic cell death(ICD),tumor-associated macrophages(TAMs)phenotype reprogramming and programmed cell death ligand 1(PD-L1)degradation.The“Gemini nanoimmunoregulators”PM@RM-T7 and PR@RM-M2 were constructed by taking the biocompatible mesoporous polydopamine(mPDA)as nanovectors to deliver metformin(Met)and toll-like receptor 7/8 agonist resiquimod(R848)to cancer cells and TAMs by specific biorecognition via wrapping of red blood cell membrane(RM)inlaid with T7or M2 peptides.mPDA/Met@RM-T7(abbreviated as PM@RM-T7)was constructed to elicit an amplified in situ ICD effect through the targeted PTT and effectively stimulated the anticancer immunity.Meanwhile,PD-L1 on the remaining cancer cells was degraded by the burst metformin to prevent immune evasion.Subsequently,mPDA/R848@RM-M2(abbreviated as PR@RM-M2)specifically recognized TAMs and reset the phenotype from M2 to M1 state,thus disrupting the immunosuppressive microenvironment and further boosting the function of cytotoxic T lymphocytes.This pair of sister nanoimmunoregulators cooperatively orchestrated the comprehensive anticancer activity,which remarkably inhibited the growth of primary and distant 4T1 tumors and prevented malignant metastasis.This study highlights the spatiotemporal cooperative modalities using multiple nanomedicines and provides a new paradigm for efficient cancer immunotherapy against metastatic-prone tumors.

A site-oriented nanosystem for active transcellular chemo-immunotherapy to prevent tumor growth and metastasis

Immunotherapy has shown promising potential in cancer therapy;however, poor delivery by nanocarriers and insufficient immune response in tumors have severely impeded its clinical application. To overcome these disadvantages, a site-specific and active transcellular drug delivery system was developed herein for chemotherapyenhanced immunotherapy. When arriving at the tumor site,the matrix metallopeptidase 2(MMP2)-responsive shell detached from the nanosystem, releasing positively charged cores. The cationic surface of the inner cores induced adsorption-meditated transcytosis, which facilitated transendothelial transportation and transcellular drug delivery into distal tumor cells. PD-L1 antibody and chemotherapeutic drugs were loaded in the outer layer and inner cores of the nanosystem, respectively, to be precisely delivered to target sites, thereby achieving synchronized delivery and siteoriented release of different anticancer agents. PD-L1 antibody released in the tumor microenvironment effectively blocked the binding of PD-L1 to its receptors on the T cell surface. Oxaliplatin and indoximod co-delivered in the cationic cores can induce immunogenic cell death and attenuate the immunosuppressive effect throughout the tumor tissues,recruiting a large amount of T cells and further enhancing the immunotherapy. The resulting synergistic antitumor response could not only efficiently inhibit the growth of primary tumors, but also help prevent metastasis of primary tumor to distant sites. This study offers a novel nano-enabled strategy for chemo-immunotherapy in immunosuppressive tumors.

Lycorine inhibits breast cancer growth and metastasis via inducing apoptosis and blocking Src/FAK-involved pathway

Breast cancer is the most commonly diagnosed cancer type worldwide among women and more than 90% of patients die from tumor metastasis. Lycorine, a natural alkaloid, has been widely reported possessing potential efficacy against cancer proliferation and metastasis. In our study, the anti-tumor potency on breast cancer was evaluated in vitro and in vivo for the first time. Our results indicated that lycorine inhibited breast cancer cells growth, migration and invasion as well as induced their apoptosis.In in vivo study, lycorine not only suppressed breast tumor growth in xenograft models and inhibited breast tumor metastasis in MDA-MB-231 tail vein model. More importantly, we found lycorine had less toxicity than first-line chemotherapy drug paclitaxel at the same effective dose in vivo. Furthermore, on mechanism, lycorine inhibited tumor cell migration and invasion via blocking the Src/FAK(focal adhesion kinase)-involved pathway. In conclusion, our study implied lycorine was a potential candidate for the treatment of breast cancer by inhibition of tumor growth and metastasis.

Oncogenic Ras/PI3K/Her2 share a common pathway in promoting cancer metastasis via inhibiting expression of p53-related ΔNp63α

Subject Code:H16With the support by the National Natural Science Foundation of China,a collaborative study by the research groups led by Prof.Xiao Zhixiong(肖智雄)from the College of Life Science,Sichuan University demonstrates thatΔNp63αis a common inhibitory target in oncogenic PI3K/Ras/Her2-induced

Self-assembled FeS-based cascade bioreactor with enhanced tumor penetration and synergistic treatments to trigger robust cancer immunotherapy

Major challenges for cancer treatment are how to effectively eliminate primary tumor and sufficiently induce immunogenic cell death(ICD)to provoke a robust immune response for metastasis control.Here,a self-assembled cascade bioreactor was developed to improve cancer treatment with enhanced tumor penetration and synergistic therapy of starvation,chemodynamic(CDT)and photothermal therapy.Ultrasmall Fe S-GOx nanodots were synthesized with glucose oxidase(GOx)as template and induced by paclitaxel(PTX)to form self-assembling Fe S-GOx@PTX(FGP)via hydrophobic interaction.After accumulated at tumor sites,FGP disassembles to smaller Fe S-GOx for enhanced deep tumor penetration.GOx maintains high enzymatic activity to catalyze glucose with assistant of oxygen to generate hydrogen peroxide(H2O2)as starvation therapy.Fenton reaction involving the regenerated H_(2)O_(2) in turn produced more hydroxyl radicals for enhanced CDT.Following near-infrared laser at 808 nm,FGPs displayed pronounced tumor inhibition in vitro and in vivo by the combination therapy.The consequent increased exposure to calreticulin amplified ICD and promoted dendritic cells maturation.In combination with anti-CTLA4 checkpoint blockade,FGP can absolutely eliminate primary tumor and avidly inhibit distant tumors due to the enhanced intratumoral infiltration of cytotoxic T lymphocytes.Our work presents a promising strategy for primary tumor and metastasis inhibition.