Connecting on Climate: A Guide to Effective Climate Change Communication

Climate change is not a new issue, but the need for meaningful and sustainable solutions is more urgent than ever. Climate communicators and mainstream leaders are still grappling with how to help Americans find meaningful, actionable paths forward and overcome the social, political, psychological, and emotional barriers that have hindered progress on climate solutions. To connect with audiences and unlock success in climate change communication, communicators need to shift their approach. Communicators need to go beyond simply providing people with the facts about climate change. They need to connect with people’s values and worldviews and put solutions at the forefront to make climate change personally relevant to Americans and those they love. With this guide, we have brought together both researchers and practitioners to consolidate the best insights and evidence about how to communicate effectively about climate change. We have combined research from the Center for Research on Environmental Decisions (CRED) at The Earth Institute, Columbia University; ecoAmerica; and other institutions with insights that ecoAmerica has gleaned from communicating about climate change and other environmental issues with mainstream Americans and their leaders. This guide presents information in a digestible, actionable form to enable communicators to “up their game” when engaging Americans on climate solutions of all types and scales

IRF4 and BATF are critical for CD8(+) T-cell function following infection with LCMV.

CD8(+) T-cell functions are critical for preventing chronic viral infections by eliminating infected cells. For healthy immune responses, beneficial destruction of infected cells must be balanced against immunopathology resulting from collateral damage to tissues. These processes are regulated by factors controlling CD8(+) T-cell function, which are still incompletely understood. Here, we show that the interferon regulatory factor 4 (IRF4) and its cooperating binding partner B-cell-activating transcription factor (BATF) are necessary for sustained CD8(+) T-cell effector function. Although Irf4(-/-) CD8(+) T cells were initially capable of proliferation, IRF4 deficiency resulted in limited CD8(+) T-cell responses after infection with the lymphocytic choriomeningitis virus. Consequently, Irf4(-/-) mice established chronic infections, but were protected from fatal immunopathology. Absence of BATF also resulted in reduced CD8(+) T-cell function, limited immunopathology, and promotion of viral persistence. These data identify the transcription factors IRF4 and BATF as major regulators of antiviral cytotoxic T-cell immunity

Targeted agents and immunotherapies: optimizing outcomes in melanoma

Treatment options for patients with metastatic melanoma, and especially BRAF-mutant melanoma, have changed dramatically in the past 5 years, with the FDA approval of eight new therapeutic agents. During this period, the treatment paradigm for BRAF-mutant disease has evolved rapidly: the standard-of-care BRAF-targeted approach has shifted from single-agent BRAF inhibition to combination therapy with a BRAF and a MEK inhibitor. Concurrently, immunotherapy has transitioned from cytokine-based treatment to antibody-mediated blockade of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and, now, the programmed cell-death protein 1 (PD-1) immune checkpoints. These changes in the treatment landscape have dramatically improved patient outcomes, with the median overall survival of patients with advanced-stage melanoma increasing from approximately 9 months before 2011 to at least 2 years - and probably longer for those with BRAF-V600-mutant disease. Herein, we review the clinical trial data that established the standard-of-care treatment approaches for advanced-stage melanoma. Mechanisms of resistance and biomarkers of response to BRAF-targeted treatments and immunotherapies are discussed, and the contrasting clinical benefits and limitations of these therapies are explored. We summarize the state of the field and outline a rational approach to frontline-treatment selection for each individual patient with BRAF-mutant melanoma

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Uncoupling interferon signaling and antigen presentation to overcome immunotherapy resistance due to JAK1 loss in melanoma.

Defects in tumor-intrinsic interferon (IFN) signaling result in failure of immune checkpoint blockade (ICB) against cancer, but these tumors may still maintain sensitivity to T cell-based adoptive cell therapy (ACT). We generated models of IFN signaling defects in B16 murine melanoma observed in patients with acquired resistance to ICB. Tumors lacking Jak1 or Jak2 did not respond to ICB, whereas ACT was effective against Jak2 KO tumors, but not Jak1 KO tumors, where both type I and II tumor IFN signaling were defective. This was a direct result of low baseline class I major histocompatibility complex (MHC I) expression in B16 and the dependency of MHC I expression on either type I or type II IFN signaling. We used genetic and pharmacologic approaches to uncouple this dependency and restore MHC I expression. Through independent mechanisms, overexpression of NLRC5 (nucleotide-binding oligomerization domain-like receptor family caspase recruitment domain containing 5) and intratumoral delivery of BO-112, a potent nanoplexed version of polyinosinic:polycytidylic acid (poly I:C), each restored the efficacy of ACT against B16-Jak1 KO tumors. BO-112 activated double-stranded RNA (dsRNA) sensing (via protein kinase R and Toll-like receptor 3) and induced MHC I expression via nuclear factor κB, independent of both IFN signaling and NLRC5. In summary, we demonstrated that in the absence of tumor IFN signaling, MHC I expression is essential and sufficient for the efficacy of ACT. For tumors lacking MHC I expression due to deficient IFN signaling, activation of dsRNA sensors by BO-112 affords an alternative approach to restore the efficacy of ACT

Dendritic cells direct circadian anti-tumor immune responses.

The process of cancer immunosurveillance is a mechanism of tumor suppression that can protect the host from cancer development throughout its lifetime1,2. Yet, it is unknown whether its effectiveness fluctuates over a single day. Here, we demonstrate that the initial time-of-day of tumor engraftment dictates ensuing tumor size across murine cancer models. Using immunodeficient mice and animals lacking lineage-specific circadian functions, we show that dendritic cells (DCs) and CD8+ T cells exert circadian anti-tumor functions that control melanoma volume. Specifically, we find that rhythmic trafficking of DCs to the tumor draining lymph node (dLN) governs a circadian response of tumor antigen-specific CD8+ T cells, which is dependent on circadian expression of the co-stimulatory molecule CD80. Consequently, cancer immunotherapy is more effective when synchronized with DC functions, shows circadian outcomes in mice and suggests similar effects in humans. These data demonstrate that circadian rhythms of anti-tumor immune components are not only critical for the control of tumor size but can also be exploited therapeutically