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Introduction: Despite recent advances, triple-negative breast cancer (TNBC) patients remain at high risk for recurrence and metastasis, which creates the need for innovative therapeutic approaches to improve patient outcomes. Cryoablation is a promising, less invasive alternative to surgical resection, capable of inducing tumor necrosis via freeze/thaw cycles. Necrotic cell death results in increased inflammatory signals and release of preserved tumor antigens, which have the potential to boost the local and systemic anti-tumor immune response. Thus, compared to surgery, cryoablation enhances the activation of T cells leading to an improved abscopal effect, defined as the occurrence of a systemic response after local treatment. We previously showed with a bilateral-tumor mouse model of TNBC that cryoablation of the primary tumor leads to increased infiltration of distant (abscopal) tumors by tumor infiltrating lymphocytes (TILs) and decreased rates of recurrence and metastasis. However, the early drivers of the cryoablation generated abscopal effect are still unknown and knowledge of the mechanism could provide insight into improving the anti-tumor immune response through pharmacologic immune modulation in addition to cryoablation. Methods: One million 4T1-12B-luciferase expressing cells were transplanted into the mammary fat pad of BALB/c mice. Two weeks later, left (primary) tumors were either resected or cryoablated. A week after the procedure, right (abscopal) and left tumors, along with spleen, tumor-draining lymph node and blood were collected and processed for flow cytometry and/or RNA-sequencing and immunofluorescence. Results: Here we show that cryoablation of mouse mammary carcinomas results in smaller abscopal tumors that harbor increased frequencies of anti-tumor cells [such as natural killer (NK) cells], accompanied by a systemic increase in the frequency of migratory conventional type 1 dendritic cells (cDC1; CD103+ XCR1+), compared to resection. The changes in cell frequencies are mirrored by the immune gene signature of the abscopal tumors, with cryoablation inducing genes involved with NK cell activation and leukocyte-mediated toxicity, including IL11ra1 and Pfr1. Conclusions: These results better define the early mechanisms through which cryoablation improves tumor elimination, which is mediated by enhanced frequencies of anti-tumoral cells such as NK and cDC1s at the abscopal tumor and in the spleen of mice treated with cryoablation, respectively. [ABSTRACT FROM AUTHOR]

Introduction: Despite recent advances, triple-negative breast cancer (TNBC) patients remain at high risk for recurrence and metastasis, which creates the need for innovative therapeutic approaches to improve patient outcomes. Cryoablation is a promising, less invasive alternative to surgical resection, capable of inducing tumor necrosis via freeze/thaw cycles. Necrotic cell death results in increased inflammatory signals and release of preserved tumor antigens, which have the potential to boost the local and systemic anti-tumor immune response. Thus, compared to surgery, cryoablation enhances the activation of T cells leading to an improved abscopal effect, defined as the occurrence of a systemic response after local treatment. We previously showed with a bilateral-tumor mouse model of TNBC that cryoablation of the primary tumor leads to increased infiltration of distant (abscopal) tumors by tumor infiltrating lymphocytes (TILs) and decreased rates of recurrence and metastasis. However, the early drivers of the cryoablation generated abscopal effect are still unknown and knowledge of the mechanism could provide insight into improving the anti-tumor immune response through pharmacologic immune modulation in addition to cryoablation. Methods: One million 4T1-12B-luciferase expressing cells were transplanted into the mammary fat pad of BALB/c mice. Two weeks later, left (primary) tumors were either resected or cryoablated. A week after the procedure, right (abscopal) and left tumors, along with spleen, tumor-draining lymph node and blood were collected and processed for flow cytometry and/or RNA-sequencing and immunofluorescence. Results: Here we show that cryoablation of mouse mammary carcinomas results in smaller abscopal tumors that harbor increased frequencies of anti-tumor cells [such as natural killer (NK) cells], accompanied by a systemic increase in the frequency of migratory conventional type 1 dendritic cells (cDC1; CD103+ XCR1+), compared to resection. The changes in cell frequencies are mirrored by the immune gene signature of the abscopal tumors, with cryoablation inducing genes involved with NK cell activation and leukocyte-mediated toxicity, including IL11ra1 and Pfr1. Conclusions: These results better define the early mechanisms through which cryoablation improves tumor elimination, which is mediated by enhanced frequencies of anti-tumoral cells such as NK and cDC1s at the abscopal tumor and in the spleen of mice treated with cryoablation, respectively. [ABSTRACT FROM AUTHOR]

Here we show that transplantation of autologous human hematopoietic fetal liver CD34[sup.+] cells into NOD/SCID mice previously implanted with human fetal thymic and liver tissues results in long-term, systemic human T-cell homeostasis. In addition, these mice show systemic repopulation with human B cells, monocytes and macrophages, and dendritic cells (DCs). T cells in these mice generate human major histocompatibility complex class I- and class II-restricted adaptive immune responses to Epstein-Barr virus (EBV) infection and are activated by human DCs to mount a potent T-cell immune response to superantigens. Administration of the superantigen toxic shock syndrome toxin 1 (TSST-1) results in the specific systemic expansion of human V[beta]2[sup.+] T cells, release of human proinflammatory cytokines and localized, specific activation and maturation of human CD11c[sup.+] dendritic cells. This represents the first demonstration of long-term systemic human T-cell reconstitution in vivo allowing for the manifestation of the differential response by human DCs to TSST-1., Author(s): Michael W Melkus [1]; Jacob D Estes [2]; Angela Padgett-Thomas [1]; Joel Gatlin [3]; Paul W Denton [1]; Florence A Othieno [1]; Anja K Wege [1]; Ashley T Haase [...]

Epstein­Barr virus (EBV)-induced lymphoproliferative disease is an important complication in the context of immune deficiency. Impaired T-cell immunity allows the outgrowth of transformed cells with the subsequent production of predominantly B-cell lymphomas. Currently there is no in vivo model that can adequately recapitulate EBV infection and its association with B-cell lymphomas. NOD/SCID mice engrafted with human CD34+ cells and reconstituted mainly with human B lymphocytes may serve as a useful xenograft model to study EBV infection and pathogenesis. We therefore infected reconstituted mice with EBV. High levels of viral DNA were detected in the peripheral blood of all infected mice. All infected mice lost weight and showed decreased activity levels. Infected mice presented large visible tumors in multiple organs, most prominently in the spleen. These tumors stained positive for human CD79a, CD20, CD30, and EBV-encoded RNAs and were light chain restricted. Their characterization is consistent with that of large cell immunoblastic lymphoma. In addition, tumor cells expressed EBNA1, LMP1, and LMP2a mRNAs, which is consistent with a type II latency program. EBV+ lymphoblastoid cell lines expressing human CD45, CD19, CD21, CD23, CD5, and CD30 were readily established from the bone marrow and spleens of infected animals. Finally, we also demonstrate that infection with an enhanced green fluorescent protein (EGFP)-tagged virus can be monitored by the detection of infected EGFP+ cells and EGFP+ tumors. These data demonstrate that NOD/SCID mice that are reconstituted with human CD34+ cells are susceptible to infection by EBV and accurately recapitulate important aspects of EBV pathogenesis. [ABSTRACT FROM AUTHOR]