Prognostic significance of primary-tumor extension, stage and grade of nuclear differentiation in patients with renal cell carcinoma

Surgery remains the preferred therapy for renal cell carcinoma. The various adjunctive or complementary therapies currently yield disappointing results. Identifying reliable prognostic factors could help in selecting patients most likely to benefit from postoperative adjuvant therapies. We reviewed the surgical records of 78 patients who had undergone radical nephrectomy with lymphadenectomy for renal cell carcinoma, matched for type of operation and histology. According to staging (TNM), 5.1% of the patients were classified as stage I, 51.3% as stage II, 29.5% as stage III and 14.5% as stage IV. Of the 78 patients 40 were T2N0 and 21 T3aN0. Tumor grading showed that 39.7% of the patients had well-differentiated tumors(G1), 41.1% moderately-differentiated (G2), and 19.2% poorly-differentiated tumors (G3). Overall actuarial survival at 5 and 10 years was 100% for stage 1; 91.3% at 5 years and 83.1% at 10 years for stage II; 45.5% and 34.1% for stage III; and 29.1% and nil for stage IV (stage II vs stage III p = 0.0001). Patients with tumors confined to the kidney (pT2N0) had better 5- and 10-year survival rates than patients with tumors infiltrating the perirenal fat (pT3aN0) (p = 0.000006). Survival differed according to nuclear grading (G1 vs G3 ; p = 0.000005; G2 vs G3; p = 0.0009). In conclusion our review identified tumor stage, primary-tumor extension, and the grade of nuclear differentiation as reliable prognostic factors in patients with renal cell carcinomas

Tumor-reactive immune cells protect against metastatic tumor and induce immunoediting of indolent but not quiescent tumor cells

Two major barriers to cancer immunotherapy include tumor-induced immune suppression mediated by myeloid-derived suppressor cells and poor immunogenicity of the tumor-expressing self-antigens. To overcome these barriers, we reprogrammed tumor-immune cell cross-talk by combined use of decitabine and adoptive immunotherapy, containing tumor-sensitized T cells and CD25+ NKT cells. Decitabine functioned to induce the expression of highly immunogenic cancer testis antigens in the tumor, while also reducing the frequency of myeloid-derived suppressor cells and the presence of CD25+ NKT cells rendered T cells, resistant to remaining myeloid-derived suppressor cells. This combinatorial therapy significantly prolonged survival of animals bearing metastatic tumor cells. Adoptive immunotherapy also induced tumor immunoediting, resulting in tumor escape and associated disease-related mortality. To identify a tumor target that is incapable of escape from the immune response, we used dormant tumor cells. We used Adriamycin chemotherapy or radiation therapy, which simultaneously induce tumor cell death and tumor dormancy. Resultant dormant cells became refractory to additional doses of Adriamycin or radiation therapy, but they remained sensitive to tumor-reactive immune cells. Importantly, we discovered that dormant tumor cells contained indolent cells that expressed low levels of Ki67 and quiescent cells that were Ki67 negative. Whereas the former were prone to tumor immunoediting and escape, the latter did not demonstrate immunoediting. Our results suggest that immunotherapy could be highly effective against quiescent dormant tumor cells. The challenge is to develop combinatorial therapies that could establish a quiescent type of tumor dormancy, which would be the best target for immunotherapy

DDR2 controls breast tumor stiffness and metastasis by regulating integrin mediated mechanotransduction in CAFs

Biomechanical changes in the tumor microenvironment influence tumor progression and metastases. Collagen content and fiber organization within the tumor stroma are major contributors to biomechanical changes (e., tumor stiffness) and correlated with tumor aggressiveness and outcome. What signals and in what cells control collagen organization within the tumors, and how, is not fully understood. We show in mouse breast tumors that the action of the collagen receptor DDR2 in CAFs controls tumor stiffness by reorganizing collagen fibers specifically at the tumor-stromal boundary. These changes were associated with lung metastases. The action of DDR2 in mouse and human CAFs, and tumors in vivo, was found to influence mechanotransduction by controlling full collagen-binding integrin activation via Rap1-mediated Talin1 and Kindlin2 recruitment. The action of DDR2 in tumor CAFs is thus critical for remodeling collagen fibers at the tumor-stromal boundary to generate a physically permissive tumor microenvironment for tumor cell invasion and metastases

Automatic Brain Tumor Segmentation using Cascaded Anisotropic Convolutional Neural Networks

A cascade of fully convolutional neural networks is proposed to segment multi-modal Magnetic Resonance (MR) images with brain tumor into background and three hierarchical regions: whole tumor, tumor core and enhancing tumor core. The cascade is designed to decompose the multi-class segmentation problem into a sequence of three binary segmentation problems according to the subregion hierarchy. The whole tumor is segmented in the first step and the bounding box of the result is used for the tumor core segmentation in the second step. The enhancing tumor core is then segmented based on the bounding box of the tumor core segmentation result. Our networks consist of multiple layers of anisotropic and dilated convolution filters, and they are combined with multi-view fusion to reduce false positives. Residual connections and multi-scale predictions are employed in these networks to boost the segmentation performance. Experiments with BraTS 2017 validation set show that the proposed method achieved average Dice scores of 0.7859, 0.9050, 0.8378 for enhancing tumor core, whole tumor and tumor core, respectively. The corresponding values for BraTS 2017 testing set were 0.7831, 0.8739, and 0.7748, respectively.Comment: 12 pages, 5 figures. MICCAI Brats Challenge 201

Osteocyte-Driven Downregulation of Snail Restrains Effects of Drd2 Inhibitors on Mammary Tumor Cells

While bone is a frequent target of breast cancer-associated metastasis, little is known about the effects of tumor-bone interactions on the efficacy of tumor-suppressing agents. Here we examined the effect of two FDA-approved dopamine modulators, fluphenazine and trifluoperazine, on mammary tumor cells, osteoclasts, osteoblasts, and osteocytes. These agents suppressed proliferation and migration of mammary tumor cells chiefly by antagonizing dopamine receptor D2 and reduced bone resorption by downregulating nuclear factor of activated T cells, cytoplasmic 1 (Nfatc1). Three-dimensional spheroid formation assays revealed that tumor cells have high affinity to osteocytes and type I collagen, and interactions with osteocytes as well as administration of fluphenazine and trifluoperazine downregulated Snail and suppressed migratory behaviors. Unlike the inhibitory action of fluphenazine and trifluoperazine on tumor growth, tumor-osteocyte interactions stimulated tumor proliferation by upregulating NFκB and Akt. In the bone microenvironment, osteocytes downregulated Snail and acted as an attractant as well as a stimulant to mammary tumor cells. These results demonstrate that tumor-osteocyte interactions strengthen dopamine receptor-mediated suppression of tumor migration but weaken its inhibition of tumor proliferation in the osteocyte-rich bone microenvironment.Significance: These findings provide novel insight into the cellular cross-talk in the bone microevironment and the effects of dopamine modulators on mammary tumor cells and osteocytes. Cancer Res; 78(14); 3865-76. ©2018 AACR

Recombinant Listeria promotes tumor rejection by CD8+ T cell-dependent remodeling of the tumor microenvironment.

Agents that remodel the tumor microenvironment (TME), prime functional tumor-specific T cells, and block inhibitory signaling pathways are essential components of effective immunotherapy. We are evaluating live-attenuated, double-deleted Listeria monocytogenes expressing tumor antigens (LADD-Ag) in the clinic. Here we show in numerous mouse models that while treatment with nonrecombinant LADD induced some changes in the TME, no antitumor efficacy was observed, even when combined with immune checkpoint blockade. In contrast, LADD-Ag promoted tumor rejection by priming tumor-specific KLRG1+PD1loCD62L- CD8+ T cells. These IFNγ-producing effector CD8+ T cells infiltrated the tumor and converted the tumor from an immunosuppressive to an inflamed microenvironment that was characterized by a decrease in regulatory T cells (Treg) levels, a proinflammatory cytokine milieu, and the shift of M2 macrophages to an inducible nitric oxide synthase (iNOS)+CD206- M1 phenotype. Remarkably, these LADD-Ag-induced tumor-specific T cells persisted for more than 2 months after primary tumor challenge and rapidly controlled secondary tumor challenge. Our results indicate that the striking antitumor efficacy observed in mice with LADD-based immunotherapy stems from TME remodeling which is a direct consequence of eliciting potent, systemic tumor-specific CD8+ T cells

Cancer therapeutic potential of combinatorial immuno- and vaso-modulatory interventions

Currently, most of the basic mechanisms governing tumor-immune system interactions, in combination with modulations of tumor-associated vasculature, are far from being completely understood. Here, we propose a mathematical model of vascularized tumor growth, where the main novelty is the modeling of the interplay between functional tumor vasculature and effector cell recruitment dynamics. Parameters are calibrated on the basis of different in vivo immunocompromised Rag1-/- and wild-type (WT) BALB/c murine tumor growth experiments. The model analysis supports that tumor vasculature normalization can be a plausible and effective strategy to treat cancer when combined with appropriate immuno-stimulations. We find that improved levels of functional tumor vasculature, potentially mediated by normalization or stress alleviation strategies, can provide beneficial outcomes in terms of tumor burden reduction and growth control. Normalization of tumor blood vessels opens a therapeutic window of opportunity to augment the antitumor immune responses, as well as to reduce the intratumoral immunosuppression and induced-hypoxia due to vascular abnormalities. The potential success of normalizing tumor-associated vasculature closely depends on the effector cell recruitment dynamics and tumor sizes. Furthermore, an arbitrary increase of initial effector cell concentration does not necessarily imply a better tumor control. We evidence the existence of an optimal concentration range of effector cells for tumor shrinkage. Based on these findings, we suggest a theory-driven therapeutic proposal that optimally combines immuno- and vaso-modulatory interventions

Tumor-derived exosomes confer antigen-specific immunosuppression in a murine delayed-type hypersensitivity model

Exosomes are endosome-derived small membrane vesicles that are secreted by most cell types including tumor cells. Tumor-derived exosomes usually contain tumor antigens and have been used as a source of tumor antigens to stimulate anti-tumor immune responses. However, many reports also suggest that tumor-derived exosomes can facilitate tumor immune evasion through different mechanisms, most of which are antigen-independent. In the present study we used a mouse model of delayed-type hypersensitivity (DTH) and demonstrated that local administration of tumor-derived exosomes carrying the model antigen chicken ovalbumin (OVA) resulted in the suppression of DTH response in an antigen-specific manner. Analysis of exosome trafficking demonstrated that following local injection, tumor-derived exosomes were internalized by CD11c+ cells and transported to the draining LN. Exosome-mediated DTH suppression is associated with increased mRNA levels of TGF-β1 and IL-4 in the draining LN. The tumor-derived exosomes examined were also found to inhibit DC maturation. Taken together, our results suggest a role for tumor-derived exosomes in inducing tumor antigen-specific immunosuppression, possibly by modulating the function of APCs. © 2011 Yang et al