IL1 Receptor Antagonist Controls Transcriptional Signature of Inflammation in Patients with Metastatic Breast Cancer.

Inflammation affects tumor immune surveillance and resistance to therapy. Here, we show that production of IL1ß in primary breast cancer tumors is linked with advanced disease and originates from tumor-infiltrating CD11c+ myeloid cells. IL1ß production is triggered by cancer cell membrane-derived TGFß. Neutralizing TGFß or IL1 receptor prevents breast cancer progression in humanized mouse model. Patients with metastatic HER2- breast cancer display a transcriptional signature of inflammation in the blood leukocytes, which is attenuated after IL1 blockade. When present in primary breast cancer tumors, this signature discriminates patients with poor clinical outcomes in two independent public datasets (TCGA and METABRIC).Significance: IL1ß orchestrates tumor-promoting inflammation in breast cancer and can be targeted in patients using an IL1 receptor antagonist. Cancer Res; 78(18); 5243-58. ©2018 AACRSee related commentary by Dinarello, p. 5200.

Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation.

In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner. Notably, prostate cancer cell irradiation triggers binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacologic inhibition of DNA-PKc blocked this interaction, increased DNA damage, and elevated prostate cancer cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized prostate cancer. Cancer Res; 77(18); 4745-54. ©2017 AACR.

DNA-PKcs phosphorylates hnRNP-A1 to facilitate the RPA-to-POT1 switch and telomere capping after replication.

The heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) has been implicated in telomere protection and telomerase activation. Recent evidence has further demonstrated that hnRNP-A1 plays a crucial role in maintaining newly replicated telomeric 3' overhangs and facilitating the switch from replication protein A (RPA) to protection of telomeres 1 (POT1). The role of hnRNP-A1 in telomere protection also involves DNA-dependent protein kinase catalytic subunit (DNA-PKcs), although the detailed regulation mechanism has not been clear. Here we report that hnRNP-A1 is phosphorylated by DNA-PKcs during the G2 and M phases and that DNA-PK-dependent hnRNP-A1 phosphorylation promotes the RPA-to-POT1 switch on telomeric single-stranded 3' overhangs. Consequently, in cells lacking hnRNP-A1 or DNA-PKcs-dependent hnRNP-A1 phosphorylation, impairment of the RPA-to-POT1 switch results in DNA damage response at telomeres during mitosis as well as induction of fragile telomeres. Taken together, our results indicate that DNA-PKcs-dependent hnRNP-A1 phosphorylation is critical for capping of the newly replicated telomeres and prevention of telomeric aberrations.

Reprogramming tumor-infiltrating dendritic cells for CD103+ CD8+ mucosal T-cell differentiation and breast cancer rejection.

Our studies showed that tumor-infiltrating dendritic cells (DC) in breast cancer drive inflammatory Th2 (iTh2) cells and protumor inflammation. Here, we show that intratumoral delivery of the ß-glucan curdlan, a ligand of dectin-1, blocks the generation of iTh2 cells and prevents breast cancer progression in vivo. Curdlan reprograms tumor-infiltrating DCs via the ligation of dectin-1, enabling the DCs to become resistant to cancer-derived thymic stromal lymphopoietin (TSLP), to produce IL-12p70, and to favor the generation of Th1 cells. DCs activated via dectin-1, but not those activated with TLR-7/8 ligand or poly I:C, induce CD8+ T cells to express CD103 (αE integrin), a ligand for cancer cells, E-cadherin. Generation of these mucosal CD8+ T cells is regulated by DC-derived integrin αvß8 and TGF-ß activation in a dectin-1-dependent fashion. These CD103+ CD8+ mucosal T cells accumulate in the tumors, thereby increasing cancer necrosis and inhibiting cancer progression in vivo in a humanized mouse model of breast cancer. Importantly, CD103+ CD8+ mucosal T cells elicited by reprogrammed DCs can reject established cancer. Thus, reprogramming tumor-infiltrating DCs represents a new strategy for cancer rejection.

Anti-tumor immune responses in immune-reconstituted mice injected with a tumor vaccine.

Homeostasis-driven proliferation of T cells is an important means of reconstituting T-cell-dependent immunity after lymphodepletion regimens, such as chemotherapy or radiotherapy. Immune-reconstituted mice that receive a tumor vaccine mount more efficient anti-tumor immune responses compared with control mice. In the present study, we evaluated the anti-tumor immune responses in immune-reconstituted mice vaccinated with inactivated leukemia cells and explored the mechanisms underlying these immune responses. Test C57BL/6 mice were lymphodepleted by irradiation and immune-reconstituted with naïve mouse spleen lymphocytes. Mice were then injected with an inactivated FBL-3 tumor cell vaccine and challenged with FBL-3 tumor cells. Anti-tumor responses were evaluated by determining the rate of tumor formation, latency, tumor size, interferon gamma levels, and macrophage and CTL cytotoxicities. When challenged with tumor cells, immune-reconstituted, vaccinated mice exhibited a significantly lower mortality, smaller average tumor volume, and a significantly longer mean survival time. They had more robust cellular immunity, reflected by higher levels of INF-γ production and higher macrophage- and CTL-mediated cytotoxicities. Our results suggest that immune reconstitution enhanced the anti-tumor immune responses in mice injected with a tumor vaccine via generation of CTLs. These results have important implications for immunotherapy used for leukemia.

Thymic stromal lymphopoietin fosters human breast tumor growth by promoting type 2 inflammation.

The human breast tumor microenvironment can display features of T helper type 2 (Th2) inflammation, and Th2 inflammation can promote tumor development. However, the molecular and cellular mechanisms contributing to Th2 inflammation in breast tumors remain unclear. Here, we show that human breast cancer cells produce thymic stromal lymphopoietin (TSLP). Breast tumor supernatants, in a TSLP-dependent manner, induce expression of OX40L on dendritic cells (DCs). OX40L(+) DCs are found in primary breast tumor infiltrates. OX40L(+) DCs drive development of inflammatory Th2 cells producing interleukin-13 and tumor necrosis factor in vitro. Antibodies neutralizing TSLP or OX40L inhibit breast tumor growth and interleukin-13 production in a xenograft model. Thus, breast cancer cell-derived TSLP contributes to the inflammatory Th2 microenvironment conducive to breast tumor development by inducing OX40L expression on DCs.

History of the biomedical studies PhD program: a joint graduate program of the Baylor Health Care system and Baylor University.

On a sweltering summer morning, throngs of people filed into Jones Theatre at Baylor University in Waco for the graduate student orientation. One could look around and notice the diversity of not only the student population, but also the disciplines being represented. Many students had stepped off planes only hours prior, but even those who had been traveling for days could not contain their excitement. As for me, I was nowhere near any of this. I was still 40 miles north of Waco in Waxahachie, having been pulled over for speeding. After 4 days of traveling with my life in my Volkswagon Jetta, all the way from San Francisco, on one of the most important days of my life, I was late. When I finally arrived at the Hooper Schafer Fine Arts Auditorium, out of breath from running all the way from the parking structure, all of the graduate students were quietly listening to the first introductory speech. I snuck into the back and sat down. My mind was racing, as I knew very little about Waco and Baylor University except for the growing accomplishments of the biomedical studies program. What little I did know about Baylor seemed so different from my very liberal upbringing in California. What would this experience be like for me? But, as I listened to the talks, met with other students, and finally met the entire biomedical studies entering class of 2007, I knew that I had made the right decision in coming to Baylor. This would be an experience unlike any other, and I was wholeheartedly open to embracing it. -Christine Morel, PhD candidate, Institute of Biomedical Studies.

Impact of comorbid anxiety and depression on quality of life and cellular immunity changes in patients with digestive tract cancers.

AIM: A study was performed to investigate the impact of comorbid anxiety and depression (CAD) on quality of life (QOL) and cellular immunity changes in patients with digestive tract cancers. METHODS: One hundred and fifty-six cases of both sexes with cancers of the digestive tract admitted between March 2001 and February 2004 in the Department of Medical Oncology, First Affiliated Hospital of Xi'an Jiaotong University were randomly enrolled in the study. Depressive and anxiety disorder diagnoses were assessed by using the Structured Clinical Interview for DSM-IV. All adult patients were evaluated with the Hamilton depressive scale (HAMD, the 24-item version), the Hamilton anxiety scale (HAMA, a modified 14-item version), quality of life questionnaire-core 30 (QLQ-C30), social support rating scale (SSRS), simple coping style questionnaire (SCSQ), and other questionnaires, respectively. In terms of HAMD > or = 20 and HAMA > or = 14, the patients were categorized, including CAD (n = 31) in group A, anxiety disorder (n = 23) in group B, depressive disorder (n = 37) in group C, and non-disorder (n = 65) in group D. Immunological parameters such as T-lymphocyte subsets and natural killer (NK) cell activities in peripheral blood were determined and compared among the four groups. RESULTS: The incidence of CAD was 21.15% in patients with digestive tract cancers. The average scores of social support was 43.67+/-7.05 for 156 cases, active coping 20.34+/-7.33, and passive coping 9.55+/-5.51. Compared with group D, subjective support was enhanced slightly in group A, but social support, objective support, and utilization of support reduced, especially utilization of support with significance (6.16 vs 7.80, P<0.05); total scores of active coping decreased, while passive coping reversed; granulocytes proliferated, monocytes declined, and lymphocytes declined significantly (32.87 vs 34.00, P<0.05); moreover, the percentage of CD3, CD4, CD8 and CD56 in T lymphocyte subsets was in lower level, respectively, and CD56 showed a significant decline in group A (26.02 vs 32.20, P<0.05), however, CD4/CD8 ratio increased. Physical function, role function, fatigue, sleeplessness and constipation had significant changes among different groups by one-way ANOVA, and group A was in poor QOL. It revealed that global health-related quality of life (QL) were positively correlated with active coping and CD56; CAD was negatively correlated with QL, active coping and CD56. Furthermore, the step-wise regression analysis suggested that utilization of support, CD56, active coping, fatigue, sleeplessness and depression were significant factors contributing to QOL. CONCLUSION: CAD, which can impair QOL and cellular immunity, occurs with a higher incidence in patients with digestive tract cancers. Hence, it is essential to improve mental health for them with specifically tailored interventions.