Feifei Luo

TLR1/TLR2 agonist induces tumor regression by reciprocal modulation of effector and regulatory T cells.

Using TLR agonists in cancer treatment can have either beneficial or detrimental effects. Therefore, it is important to determine their effect on the tumor growth and understand the underlying mechanisms in animal tumor models. In this study, we report a general immunotherapeutic activity of a synthetic bacterial lipoprotein (BLP), a TLR1/TLR2 agonist, on established lung carcinoma, leukemia, and melanoma in mice. Systemic treatment of 3LL tumor-bearing mice with BLP, but not LPS, led to a dose-dependent tumor regression and a long-lasting protective response against tumor rechallenge. The BLP-mediated tumor remission was neither mediated by a direct tumoricidal activity nor by innate immune cells, because it lacked therapeutic effect in immunodeficient SCID mice. Instead, BLP treatment reduced the suppressive function of Foxp3+ regulatory T cells (Tregs) and enhanced the cytotoxicity of tumor-specific CTL in vitro and in vivo. Furthermore, adoptive cotransfer of BLP-pretreated but not untreated CTL and Tregs from wild-type but not from TLR2−/− mice was sufficient to restore antitumor immunity in SCID mice by reciprocally modulating Treg and CTL function. These results demonstrate that the TLR1/TLR2 agonist BLP may have a general tumor therapeutic property involving reciprocal downregulation of Treg and upregulation of CTL function. This property may play an important role in the development of novel antitumor strategies.

Low-dose curcumin leads to the inhibition of tumor growth via enhancing CTL-mediated antitumor immunity.

Curcumin, a yellow pigment extracted from turmeric, is widely used to inhibit tumor progression. Since it can either promote or suppress the immune system, how curcumin affects the immune system in tumor-bearing bodies is not yet clear. Our study found that tumor-bearing mice treated consecutively once a day with low-dose curcumin for ten days led to a retarded tumor growth and a longer survival, which might be contributed to T cell-mediated adaptive immune response. The in vitro study also showed that a high-dose curcumin decreases T cells whereas a low-dose increases T cells derived from 3LL tumor-bearing mice, especially CD8+ T cells. Accordingly, these increased CD8+ T cells exhibited the enhancement of IFN-γ secretion, proliferation and cytotoxicity specifically against 3LL tumor cells, which may result in the success of antitumor immunity. Our research demonstrated a beneficial effect of curcumin on CD8+ T cells derived from tumor-bearing mice, which can provide a potential application in anti-tumor therapy.

Trichosanthin enhances anti-tumor immune response in a murine Lewis lung cancer model by boosting the interaction between TSLC1 and CRTAM.

Trichosanthin (TCS), extracted from the Chinese medicinal herb Trichosanthes kirilowi, has shown promise for the inhibition of tumor growth. However, its immunomodulatory effect on tumor–host interaction remains unknown. In this study, we focused on the effect of TCS on murine anti-tumor immune response in the 3LL Lewis lung carcinoma tumor model and explored the possible molecular pathways involved. In addition to inhibiting cell proliferation and inducing apoptosis in the 3LL tumor, TCS retarded tumor growth and prolonged mouse survival more significantly in C57BL/6 immunocompetent mice than in nude mice. This reflected the fact that the host immune system was involved in tumor eradication. Using FACS analysis, we found that TCS increased the percentage of effector T cells, particularly Interferon-gamma (IFN-γ) producing CD4+ and CD8+ T cells from tumor-bearing mice. TCS also promoted the vigorous proliferation of antigen-specific effector T cells, markedly increased Th1 cytokine secretion and elicited more memory T cells in tumor-bearing mice, consequently enhancing the anti-tumor response and inducing immune protection. Furthermore, we found that TCS upregulated the expression of tumor suppressor in lung cancer 1 (TSLC1) in 3LL tumor cells and the expression of its ligand, class I-restricted T cell-associated molecule (CRTAM), in effector T cells. Blocking TSLC1 expression with small interfering RNA (siRNA) significantly eliminated the effects of TCS on the proliferation and cytokine secretion of effector T cells, suggesting that TCS enhances anti-tumor immune response at least partially by boosting the interaction between TSLC1 and CRTAM. Collectively, our data demonstrate that TCS not only affects tumor cells directly, but also enhances anti-tumor immunity via the interaction between TSLC1 and CRTAM. These findings may lead to the development of a novel approach for tumor regression.

Systemic injection of TLR1/2 agonist improves adoptive antigen-specific T cell therapy in glioma-bearing mice

Adoptive immunotherapy is an attractive strategy for glioma treatment. However, some obstacles still need be overcome. In this study, GL261-bearing mice treated with adoptively transferred antigen-specific T cells and systemic injection of bacterial lipoprotein (BLP), a TLR1/2 agonist, got a long-term survival and even immune protection. By analyzing adoptive T cells, it was found that BLP maintained T cell survival, proliferation and anti-tumor efficacy in the brains of tumor-bearing hosts. Moreover, tumor microenvironment was modified by up-regulating IFN-γ-secreting CD8+ T cells and down-regulating MDSC, which might be related with high CXCL10 and low CCL2 expression. In addition, TLR2 deficiency abrogated therapeutic effect with increased MDSC accumulation and decreased IFN-γ-secreting CD8+ T cells in the brains. Thus, the systemic injection of BLP could improve the adoptive T cell therapy by maintaining T cell persistence, modifying the tumor microenvironment and even inducing systemic anti-tumor immunity, which might offer a clinically promising immunotherapeutic strategy for glioma.

Bifunctional αHER2/CD3 RNA-engineered CART-like human T cells specifically eliminate HER2 + gastric cancer

Bifunctional αHER2/CD3 RNA-engineered CART-like human T cells specifically eliminate HER2 + gastric cancer

Glycocalyx-Mimicking Nanoparticles Improve Anti-PD-L1 Cancer Immunotherapy through Reversion of Tumor-Associated Macrophages

Immune checkpoint blockade by anti-PD-L1 monoclonal antibody (αPD-L1) has achieved unprecedented clinical benefits in certain cancers, whereas the therapeutic efficacy is often hindered by immunosuppressive tumor microenvironment mediated by tumor-associated macrophages (TAMs), which leads to innate resistance to this approach. To improve checkpoint blockade efficacy, the amphiphilic diblock copolymers poly(mannopyranoside/galactopyranoside methacrylate)- block-polystyrene are prepared by RAFT polymerization, which are sequentially self-assembled into glycocalyx-mimicking nanoparticles (GNPs) to neutralize TAMs. It is shown that GNPs can be specifically internalized by TAMs via lectin receptors, which results in upregulation of immunostimulatory IL-12 and downregulation of immunosuppressive IL-10, arginase 1, and CCL22, indicating functional reversion of protumor TAMs toward antitumor phenotype. The reversion of TAMs is proved to be mainly controlled by suppressing STAT6 and activating NF-κB phosphorylation. In vivo therapeutic studies have demonstrated that GNPs significantly enhance the therapeutic efficacy of αPD-L1 cancer therapy by reduction of tumor burden. Moreover, combination therapies with GNPs and αPD-L1 greatly improve immunosuppressive tumor microenvironment by reciprocal modulation of tumor-infiltrating effector and regulatory T cells. Notably, for the first time, our results demonstrate the reversion of TAMs and improvement of αPD-L1 cancer therapy by synthetic carbohydrate-containing nanomaterials. This research highlights a promising strategy for optimizing immune checkpoint blockade in cancer immunotherapy.

Biological Response Modifier in Cancer Immunotherapy

Biological response modifiers (BRMs) emerge as a lay of new compounds or approaches used in improving cancer immunotherapy. Evidences highlight that cytokines, Toll-like receptor (TLR) signaling, and noncoding RNAs are of crucial roles in modulating antitumor immune response and cancer-related chronic inflammation, and BRMs based on them have been explored. In particular, besides some cytokines like IFN-α and IL-2, several Toll-like receptor (TLR) agonists like BCG, MPL, and imiquimod are also licensed to be used in patients with several malignancies nowadays, and the first artificial small noncoding RNA (microRNA) mimic, MXR34, has entered phase I clinical study against liver cancer, implying their potential application in cancer therapy. According to amounts of original data, this chapter will review the regulatory roles of TLR signaling, some noncoding RNAs, and several key cytokines in cancer and cancer-related immune response, as well as the clinical cases in cancer therapy based on them.

MiR-15a/16 deficiency enhances anti-tumor immunity of glioma-infiltrating CD8+ T cells through targeting mTOR

MiR‐15a/16, a miRNA cluster located at chromosome 13q14, has been reported to act as an immune regulator in inflammatory disorders besides its aberrant expression in cancers. However, little is known about its regulation in tumor‐infiltrating immune cells. In our study, using an orthotropic GL261 mouse glioma model, we found that miR‐15a/16 deficiency in host inhibited tumor growth and prolonged mice survival, which might be associated with the accumulation of tumor‐infiltrating CD8+ T cells. More importantly, tumor‐infiltrating CD8+ T cells without miR‐15a/16 showed lower expression of PD‐1, Tim‐3 and LAG‐3, and stronger secretion of IFN‐γ, IL‐2 and TNF‐α than WT tumor‐infiltrating CD8+ T cells. Also, our in vitro experiments further confirmed that miR‐15a/16−/− CD8+ T displayed higher active phenotypes, more cytokines secretion and faster expansion, compared to WT CD8+ T cells. Mechanismly, mTOR was identified as a target gene of miR‐15a/16 to negatively regulate the activation of CD8+ T cells. Taken together, these data suggest that miR‐15a/16 deficiency resists the exhaustion and maintains the activation of glioma‐infiltrating CD8+ T cells to alleviate glioma progression via targeting mTOR. Our findings provide evidence for the potential immunotherapy through targeting miR‐15a/16 in tumor‐infiltrating immune cells.

New Chimeric Antigen Receptor Design for Solid Tumors

In recent years, chimeric antigen receptor (CAR) T-cell therapy has become popular in immunotherapy, particularly after its tremendous success in the treatment of lineage-restricted hematologic cancers. However, the application of CAR T-cell therapy for solid tumors has not reached its full potential because of the lack of specific tumor antigens and inhibitory factors in suppressive tumor microenvironment (TME) (e.g., programmed death ligand-1, myeloid-derived suppressor cells, and transforming growth factor-β). In this review, we include some limitations in CAR design, such as tumor heterogeneity, indefinite spatial distance between CAR T-cell and its target cell, and suppressive TME. We also summarize some new approaches to overcome these hurdles, including targeting neoantigens and/or multiple antigens at once and depleting some inhibitory factors.

Pseudomonas aeruginosa Mannose-Sensitive Hemagglutinin Promotes T-Cell Response via Toll-Like Receptor 4–Mediated Dendritic Cells to Slow Tumor Progression in Mice

Pseudomonas aeruginosa–mannose-sensitive hemagglutinin (PA-MSHA) as a drug may kill tumor cells and has been used clinically. However, the antitumor immune response of PA-MSHA is not completely understood. In this study, we found that treating Lewis lung carcinoma (3LL)-bearing mice with PA-MSHA plus 3LL antigen led to slower tumor progression and longer survival. After PA-MSHA treatment, T-cell number and dendritic cell maturation were both increased significantly at the tumor site. In addition, PA-MSHA in vitro stimulation resulted in the maturation of bone marrow–derived dendritic cells (BMDCs) from naive mice, showing higher costimulatory molecule expression, more cytokine secretion, lower endocytic activity, and stronger capacity to enhance T-cell activation. Toll-like receptor (TLR)4 but not TLR2 was required in the maturation process. More importantly, PA-MSHA–induced DCs were essential for PA-MSHA to enhance activation, expansion, and interferon (IFN)-γ secretion of TLR4-mediated T cells, which play a role in the antitumor effect of PA-MSHA. Thus, this study reveals PA-MSHA as a novel TLR4 agonist that elicits antitumor immune response to slow tumor progression.