CD91-mediated reprogramming of DCs by immunogenic heat shock proteins requires the kinases AXL and Fgr.

Immune responses to tumors, comprising adaptive T cells and innate NK cells, arise very early in tumorigeneses and prior to detection of palpable tumors or before tissue pathology is evident. Yet, how nascent tumors evoke dendritic cell maturation and the resulting cytokine responses that are necessary for these effector anti-tumor immune responses is unknown. We have previously shown that CD91 expression on dendritic cells is important for immune surveillance, specifically for generating T cell and NK cell responses to nascent tumors.

CD91 and Its Ligand gp96 Confer Cross-Priming Capabilities to Multiple APCs during Immune Responses to Nascent, Emerging Tumors.

During cancer immunosurveillance, dendritic cells (DC) play a central role in orchestrating T-cell responses against emerging tumors. Capture of miniscule amounts of antigen along with tumor-initiated costimulatory signals can drive maturation of DCs. Expression of CD91 on DCs is essential in cross-priming of T-cell responses in the context of nascent tumors.

Tunable heat shock protein-mediated NK cell responses are orchestrated by STAT1 in Antigen Presenting Cells.

The release of Heat Shock Proteins (HSPs) from aberrant cells can initiate immune responses following engagement of the HSPs with antigen presenting cells (APCs). This is an important mechanism for cancer immunosurveillance and can also be modeled by vaccination with HSPs through various routes, targeting specific APCs expressing the HSP receptor CD91. Immunological outcomes can be varied as a result of the broad expression of CD91 in different dendritic cell and macrophage populations.

CD91 on dendritic cells governs immunosurveillance of nascent, emerging tumors.

The immune system detects aberrant, premalignant cells and eliminates them before the development of cancer. Immune cells, including T cells, have been shown to be critical components in eradicating these aberrant cells, and when absent in the host, incidence of cancer increases. Here, we show that CD91, a receptor expressed on antigen-presenting cells, is required for priming immune responses to nascent, emerging tumors.

Cutting Edge: The Heat Shock Protein gp96 Activates Inflammasome-Signaling Platforms in APCs.

Several heat shock proteins (HSPs) prime immune responses, which are, in part, a result of activation of APCs. APCs respond to these immunogenic HSPs by upregulating costimulatory molecules and secreting cytokines, including IL-1β. These HSP-mediated responses are central mediators in pathological conditions ranging from cancer, sterile inflammation associated with trauma, and rheumatoid arthritis.

HSPs drive dichotomous T-cell immune responses via DNA methylome remodelling in antigen presenting cells.

Immune responses primed by endogenous heat shock proteins, specifically gp96, can be varied, and mechanisms controlling these responses have not been defined. Immunization with low doses of gp96 primes T helper type 1 (Th1) immune responses, whereas high-dose immunization primes responses characterized by regulatory T (Treg) cells and immunosuppression. Here we show gp96 preferentially engages conventional and plasmacytoid dendritic cells (pDCs) under low and high doses, respectively, through CD91.

Phenotypically distinct helper NK cells are required for gp96-mediated anti-tumor immunity.

A number of Heat Shock Proteins (HSPs), in the extracellular environment, are immunogenic. Following cross-presentation of HSP-chaperoned peptides by CD91(+) antigen presenting cells (APCs), T cells are primed with specificity for the derivative antigen-bearing cell. Accordingly, tumor-derived HSPs are in clinical trials for cancer immunotherapy.

Radio-responsive tumors exhibit greater intratumoral immune activity than nonresponsive tumors.

Radiation therapy (RT) continues to be a cornerstone in the treatment for many cancers. Unfortunately, not all individuals respond effectively to RT resulting clinically in two groups consisting of nonresponders (progressive disease) and responders (tumor control/cure). The mechanisms that govern the outcome of radiotherapy are poorly understood.

Generation of a dual-functioning antitumor immune response in the peritoneal cavity.

Tumor cell metastasis to the peritoneal cavity is observed in patients with tumors of peritoneal organs, particularly colon and ovarian tumors. Following release into the peritoneal cavity, tumor cells rapidly attach to the omentum, a tissue consisting of immune aggregates embedded in adipose tissue. Despite their proximity to potential immune effector cells, tumor cells grow aggressively on these immune aggregates.

IFN-γ mediates the antitumor effects of radiation therapy in a murine colon tumor.

Cancer treatments using ionizing radiation (IR) therapy are thought to act primarily through the induction of tumor cell damage at a molecular level. However, a new concept has recently emerged, suggesting that the immune system is required for effective IR therapy. Our work here has identified interferon gamma (IFN-γ) as an essential cytokine for the efficacy of IR therapy.

Local expression of interleukin-2 by B16 melanoma cells results in decreased tumour growth and long-term tumour dormancy.

The tumour microenvironment is complex containing not only neoplastic cells but also a variety of host cells. The heterogeneous infiltrating immune cells include subsets of cells with opposing functions, whose activities are mediated either directly or through the cytokines they produce. Systemic delivery of cytokines such as interleukin-2 ( IL-2) has been used clinically to enhance anti-tumour responses, but these molecules are generally thought to have evolved to act locally in a paracrine fashion.

Imaging of vascular development in early mouse decidua and its association with leukocytes and trophoblasts.

In species with endometrial decidualization and hemochorial placentation (humans, mice, and others), leukocytes localize to early implant sites and contribute to decidual angiogenesis, spiral arterial remodeling, and trophoblast invasion. Relationships between leukocytes, trophoblasts, and the decidual vasculature are not fully defined. Early C57BL/6J implant sites were analyzed by flow cytometry to define leukocyte subsets and by whole-mount immunohistochemistry to visualize relationships between leukocytes, decidual vessels, and trophoblasts.

Omental immune aggregates and tumor metastasis within the peritoneal cavity.

The omentum, an important peritoneal tissue, is studded with a high number of immune aggregates, or "milky spots," the number, function, and phenotype of which is largely unknown. We have analyzed the immune composition on the normal omentum and also have shown that both free immune cells and tumor cells in the peritoneal fluid bind preferentially to these immune aggregates. This binding may be mediated by the network of collagen I fibers, which overlay these areas.