Decreased Suppression and Increased Phosphorylated STAT3 in Regulatory T Cells are Associated with Benefit from Adjuvant PD-1 Blockade in Resected Metastatic Melanoma.

Purpose: PD-1 blockade induces durable responses in patients with metastatic melanoma and prolongs relapse-free survival in patients with resected melanoma; however, current biomarkers do not consistently associate with patient responses. In this study, we investigated the impact of nivolumab therapy on peripheral blood regulatory T cells (Treg) and its relation to patient outcomes.

Experimental Design: Peripheral blood Tregs and conventional CD4 T cells from patients with resected high-risk melanoma treated with adjuvant nivolumab were assessed for gene expression changes by RNA-seq.

Radiation-induced autophagy potentiates immunotherapy of cancer via up-regulation of mannose 6-phosphate receptor on tumor cells in mice.

There is a significant body of evidence demonstrating that radiation therapy (XRT) enhances the effect of immune therapy. However, the precise mechanisms by which XRT potentiates the immunotherapy of cancer remain elusive. Here, we report that XRT potentiates the effect of immune therapy via induction of autophagy and resultant trafficking of mannose-6-phopsphate receptor (MPR) to the cell surface.

Oxidized lipids block antigen cross-presentation by dendritic cells in cancer.

Cross-presentation is one of the main features of dendritic cells (DCs), which is critically important for the development of spontaneous and therapy-inducible antitumor immune responses. Patients, at early stages of cancer, have normal presence of DCs. However, the difficulties in the development of antitumor responses in patients with low tumor burden raised the question of the mechanisms of DC dysfunction.

Novel mechanism of synergistic effects of conventional chemotherapy and immune therapy of cancer.

There is mounting evidence to support the use of a combination of immunotherapy with chemotherapy in the treatment of various types of cancers. However, the mechanism(s), by which these modalities are synergized, are not fully understood. In this review, we discuss several possible mechanisms of the combined effect of immunotherapy and chemotherapy of cancer.

The role of mannose-6-phosphate receptor and autophagy in influencing the outcome of combination therapy.

Combining two different treatment modalities for targeting malignancies is gaining importance, with preclinical/clinical results indicating higher success rates in eradicating tumors or having longer remission periods. A better understanding of the synergy between the treatments helps in optimizing the dose and time of administration. We found that chemotherapy enhanced the levels of insulin-like growth factor 2 receptor/cation-independent mannose-6-phosphate receptor (IGF2R) on the surface of tumor cells, which leads to better tumor targeting by cytotoxic T cells (CTLs).

Autophagy induced by conventional chemotherapy mediates tumor cell sensitivity to immunotherapy.

Autophagy attenuates the efficacy of conventional chemotherapy but its effects on immunotherapy have been little studied. Here, we report that chemotherapy renders tumor cells more susceptible to lysis by CTL in vivo. Moreover, bystander tumor cells that did not express antigen were killed by CTL.

Therapeutic effect of intratumoral administration of DCs with conditional expression of combination of different cytokines.

In this study, we tested the effect of intratumoral administration of dendritic cells (DCs) with inducible expression of different cytokines, using the novel Rheoswitch Therapeutic System on the experimental models of renal cell cancer (RENCA) and MethA sarcoma. Intratumoral injection of DCs, engineered to express IL-12, IL-21, or IFN-α, showed potent therapeutic effect against established tumor. This effect was associated with the induction of potent tumor antigen-specific CD8+ T-cell responses, as well as the infiltration of tumors with CD4+ and CD8+ T cells but not with the cytotoxic activity of DCs.

Tumor-infiltrating myeloid cells induce tumor cell resistance to cytotoxic T cells in mice.

Cancer immunotherapeutic approaches induce tumor-specific immune responses, in particular CTL responses, in many patients treated. However, such approaches are clinically beneficial to only a few patients. We set out to investigate one possible explanation for the failure of CTLs to eliminate tumors, specifically, the concept that this failure is not dependent on inhibition of T cell function.

Combination of external beam radiotherapy (EBRT) with intratumoral injection of dendritic cells as neo-adjuvant treatment of high-risk soft tissue sarcoma patients.

Purpose: The goal of this study was to determine the effect of combination of intratumoral administration of dendritic cells (DC) and fractionated external beam radiation (EBRT) on tumor-specific immune responses in patients with soft-tissue sarcoma (STS).

Methods And Material: Seventeen patients with large (>5 cm) high-grade STS were enrolled in the study. They were treated in the neoadjuvant setting with 5,040 cGy of EBRT, split into 28 fractions and delivered 5 days per week, combined with intratumoral injection of 10(7) DCs followed by complete resection.

Bryostatin-1, a naturally occurring antineoplastic agent, acts as a Toll-like receptor 4 (TLR-4) ligand and induces unique cytokines and chemokines in dendritic cells.

Bryostatin-1 (Bryo-1), a natural macrocyclic lactone, is clinically used as an anti-cancer agent. In this study, we demonstrate for the first time that Bryo-1 acts as a Toll-like receptor 4 (TLR4) ligand. Interestingly, activation of bone marrow-derived dendritic cells (in vitro with Bryo-1) led to a TLR4-dependent biphasic activation of nuclear factor-κB (NF-κB) and the unique induction of cytokines (IL-5, IL-6, and IL-10) and chemokines, including RANTES (regulated on activation normal T cell expressed and secreted) and macrophage inflammatory protein 1α (MIP1-α).

Mechanism of synergistic effect of chemotherapy and immunotherapy of cancer.

In recent years, the combination of cancer immunotherapy with standard therapeutic modality is gaining credibility due to a number of clinical trials demonstrating therapeutic success of such combination therapies. However, the mechanism of this phenomenon is poorly understood. Here, we will discuss recent findings that suggest novel mechanisms of synergistic effect of cancer immunotherapy and chemotherapy.

Plumbagin-induced apoptosis in lymphocytes is mediated through increased reactive oxygen species production, upregulation of Fas, and activation of the caspase cascade.

Extracts from plants containing plumbagin (PLB) continue to be used as a treatment of a number of chronic immunologically-based diseases. However, most of these claims are supported only by anecdotal evidence with few scientific reports describing the mechanism of action or the efficacy of plumbagin in the suppression of the immune response. In the current study, we tested the hypothesis that plumbagin-induced suppression of the immune response was mediated through the induction of apoptosis.

Chemotherapy enhances tumor cell susceptibility to CTL-mediated killing during cancer immunotherapy in mice.

Cancer immunotherapy faces a serious challenge because of low clinical efficacy. Recently, a number of clinical studies have reported the serendipitous finding of high rates of objective clinical response when cancer vaccines are combined with chemotherapy in patients with different types of cancers. However, the mechanism of this phenomenon remains unclear.

Molecular events in the activation of B cells and macrophages by a non-microbial TLR4 agonist, G1-4A from Tinospora cordifolia.

G1-4A, a polysaccharide from an Indian medicinal plant Tinospora cordifolia, was recently shown to protect mice against septic shock by modulating the proinflammatory cytokines. G1-4A also activated B cells polyclonally. The present report describes in detail the molecular events associated with G1-4A-induced immunomodulation in vitro and in vivo.

Combined modality immunotherapy and chemotherapy: a new perspective.

The results of recent clinical trials have demonstrated that cancer vaccines continue to struggle to achieve tangible clinical benefits as monotherapy. Tumor-induced abnormalities in the immune system hamper anti-tumor T cell responses limiting the effectiveness of cancer immunotherapy. Recently, evidence has been mounting to suggest that immunotherapy has the possibility of achieving better success when used in combination with conventional chemotherapy.

Role of CD4(+)CD25(+) T regulatory cells in IL-2-induced vascular leak.

T regulatory cells (CD4(+)CD25(+)) play an important role in the regulation of the immune response. However, little is known about the ability of T regulatory cells to regulate endothelial cell (EC) damage following activation of lymphocytes with IL-2. Therefore, in the current study, we examined the role of T regulatory cells and the subsequent T(h)1/T(h)2 bias in IL-2-mediated EC injury using the well-characterized C57BL/6 (T(h)1-biased) and BALB/c (T(h)2-biased) models.