No abstract

The most widely held explanation for the efficacy of local radiotherapy (RT) is based on direct cytotoxicity to cancer cells through the induction of lethal DNA damage. Recent studies have shown that local ablative radiation of established tumors can lead to increased T-cell priming and T-cell-dependent tumor regression, but the underlying mechanism remains unclear. Here, we describe an essential role for type I IFN in local RT-mediated tumor control. We show that ablative RT increases intratumoral production of IFN-b and, more surprisingly, the antitumor effect of RT is abolished in type I IFN nonresponsive hosts. Furthermore, the major target of RTinduced type I IFN is the hematopoietic compartment. RT drastically enhances the cross-priming capacity of tumor-infiltrating dendritic cells (TIDC) from wild-type mice but not type I IFN receptor-deficient mice. The enhanced cross-priming ability of TIDCs after RT was dependent on autocrine production of type I IFNs. By using adenoviral-mediated expression of IFN-b, we show that delivery of exogenous IFN-b into the tumor tissue in the absence of RT is also sufficient to selectively expand antigen-specific T cells leading to complete tumor regression. Our study reveals that local high-dose RT can trigger production of type I IFN that initiates a cascading innate and adaptive immune attack on the tumor. Cancer Res; 71(7); 2488-96. Ó2011 AACR.

Neonates suffer high morbidity and mortality in infection, presumably because of the lack of a fully developed adaptive and innate immune system. Evidence of poor innate responses in neonates has been shown by using a model that sensitizes the host to Toll-like receptor (TLR)-mediated inflammation with D-galactosamine (DGalN). However, we show that neonatal mice demonstrate much stronger inflammatory responses than adult mice in response to LPS stimulation, and such hypersensitivity extends to other TLR agonists including actual viral infection. Our study reveals that the ensuing inflammatory reaction after D-GalN sensitization reflects preferential toxicity of D-GalN to adult liver cells, rather than accurately reflecting the TLR response to LPS. We show further that an uncontrolled proinflammatory innate response due to inadequate T cells makes neonates more vulnerable to TLR agonists or viral infection. Remarkably, through transfer of T cells into neonates or depletion of T cells in adult mice, we show that T cells are sufficient and necessary to control the early inflammatory response to LPS. Therefore, neonates might suffer from the unleashed innate responses caused by an insufficient number of T cells, which leads to increased morbidity and mortality.

Children of BRCA mutation carriers learn of their parents genetic test results many years before preventive interventions are indicated. Further research is needed to examine how young individuals understand this information and its psychosocial impact and influence on subsequent lifestyle and health behaviors.

Toll-like receptors (TLRs) recognize conserved microbial structures called pathogen-associated molecular patterns. Signaling from TLRs leads to upregulation of co-stimulatory molecules for better priming of T cells and secretion of inflammatory cytokines by innate immune cells 1-4 . Lymphocytedeficient hosts often die of acute infection, presumably owing to their lack of an adaptive immune response to effectively clear pathogens. However, we show here that an unleashed innate immune response due to the absence of residential T cells can also be a direct cause of death. Viral infection or administration of poly(I:C), a ligand for TLR3, led to cytokine storm in T-cell-or lymphocyte-deficient mice in a fashion dependent on NK cells and tumor necrosis factor. We have further shown, through the depletion of CD4 + and CD8 + cells in wild-type mice and the transfer of T lymphocytes into Rag-1-deficient mice, respectively, that T cells are both necessary and sufficient to temper the early innate response. In addition to the effects of natural regulatory T cells, close contact of resting CD4 + CD25 − Foxp3 − or CD8 + T cells with innate cells could also suppress the cytokine surge by various innate cells in an antigen-independent fashion. Therefore, adaptive immune cells have an unexpected role in tempering initial innate responses.To study the early innate response, we infected nude mice and wild-type mice with MHV-A59, a coronavirus that primarily infects mouse liver and brain 5,6 . Nude mice died at a sublethal dose of virus as compared with wild-type mice (Fig. 1a). We presumed that lack of T cells might permit vigorous progression of the viral infection, enough to kill the host. To our surprise, the virus titer in the liver was not significantly higher in nude mice than in wild-type mice (Fig. 1b). To determine the cause of death, we collected liver and brain tissues and assessed them by H&E staining, but we did not observe any major pathology (data not shown). As a functional readout for organ damage after infection, we measured the concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), but we detected only mild increases in nude mice as compared to wild-type mice, insufficient to explain the elevated death rate of the former (Supplementary Fig. 1). This raised the intriguing possibility that the immunocompromised mice might actually die due to cytokine storm. To test that, the sera of mice were collected and cytokine levels were determined on days 2 and 4. Higher abundances of proinflammatory cytokines were detected in T cell-deficient mice than in wild-type mice (n = 16) on both day 2 ( Fig. 1c and Supplementary Fig. 2) and day 4 (data not shown).

Metastatic disease is the major cause of morbidity and mortality in cancer. Although surgery, chemotherapy, or radiation can often control primary tumor growth, successful eradication of disseminated metastases remains rare. We have now tested whether direct targeting tumor tissues to generate antitumor immune response before surgical excision produces sufficient CTL against micrometastases. One unsolved problem is whether such response allows coming CTL to be educated and then exit the tumor site. Another unsolved problem is whether these CTL can then patrol and effectively eliminate spontaneously metastasized tumor cells in the periphery. In this study, we have shown that adenovirus-expressing TNFSF14 [LIGHT (name derived from homologous to lymphotoxins, shows inducible expression, and competes with herpes simplex virus glycoprotein D for herpes virus entry mediator, a receptor expressed by T lymphocytes); Ad-LIGHT] inoculated directly into primary 4T1 tumor, a highly aggressive, spontaneously metastasizing mammary carcinoma, followed by surgical removal of the primary tumor can eradicate established and disseminated metastatic tumor cells in the peripheral tissues. Furthermore, we clearly show with a fibrosarcoma model Ag104Ld that local treatment can generate plenty of tumor-specific CTL that exit the primary tumor and infiltrate distal tumors to completely eradicate distal tumors. Therefore, targeting the primary tumor with Ad-LIGHT before surgical excision is a new strategy to elicit better immune response for the eradication of spontaneous metastases.

Current dogma holds that the innate immune system primes the adaptive immune system in response to infection, which in turn amplifies innate responses in a positive loop to effectively control pathogens. Therefore, it is accepted in most cases that T-cell deficient hosts die of acute infection because of the impaired ability of the innate immune system to control pathogens. Recent studies, however, reveal that adaptive immune cells actively dampen initial innate responses. In contrast to current understanding, there is now evidence that an insufficient number of T cells results in loss of control of innate immune responses. This raises new questions regarding the, as of yet underappreciated, role of the adaptive immune system in early infection and inflammation.

For quantifying noninvasive fat reduction, all available methods had significant limitations: photographic comparisons were subjective; circumference or caliper measurements were confounded; ultrasound was operator dependent; MRI was expensive; computed models and simulations were in early development. As new technologies are developed, the need for reliable, accurate and practical measures of subcutaneous fat will increase. Lasers Surg. Med. 50:96-110, 2018. © 2017 Wiley Periodicals, Inc.