In 2015, the European Network for the Study of Cholangiocarcinoma (ENSCCA) was founded with the aim of setting up a pan-European-wide interdisciplinary cooperative network to address the CCA problem at basic, translational, and clinical levels. Its first initiative was the creation of the Clinical ENSCCA Registry in 2016 to describe in detail the natural course of CCA in Europe, determine potential risk factors, improve the current classification system, investigate early and non-invasive accurate tumor biomarkers for diagnosis and to estimate prognosis, compare the effectiveness of therapies, and select patients for clinical trials.

“CCA is a rare cancer, but its incidence is increasing worldwide, and we need to stop treating it as an orphan disease,” explained lead investigator Dr. Jesus M. Banales, Professor Ikerbasque at Biodonostia, University of Navarra and CIBERehd, Spain. “Although CCA constitutes a major challenge for clinicians, scientists, national health systems, and society, there is a lack of coordinated multidisciplinary pan-European studies. We therefore used the ENSCCA registry to gather vital information.”

In the most comprehensive international observational study to date, investigators evaluated the natural course of histologically proven CCA in more than 2,200 patients who were diagnosed between 2010-2019 and whose details were included in the ENSCCA registry. The data were contributed by 26 referral hospitals in 11 European countries. At diagnosis, 42.2% of patients had local disease, 29.4% had locally advanced disease, and 28.4% had metastatic disease. They compared general and tumor-type specific features at diagnosis, risk factors, biomarker accuracy, as well as the similarities and differences between the three CCA subtypes based on the latest World Health Organization classification according to their anatomical origin (intrahepatic, perihilar, or distal), and a comparison of patient management and outcomes.

The results suggest that the location of CCA tumors along the biliary tree is associated with different risk factors and tumor features. Diagnoses need invasive confirmations by biopsy or cytology, as blood tests for tumor biomarkers show low sensitivity in early stages. Surgical resection remains the only potentially curative therapy, although cure is unlikely with involvement of resection margins or lymph node invasion. Investigators noted that chemotherapy increased patients’ life expectancy compared to patients receiving best supportive care. They also noted that deterioration of the patient’s performance status (ECOG), the presence of metastases, and increased levels of the tumor marker CA19-9 independently affected the outcome.

A comparative analysis of risk factors of the three different locations of CCA tumors revealed some potential lifestyle-related risk factors such as alcohol excess, smoking, overweight/obesity, diabetes, etc. These are highly prevalent in Europe and could predispose at-risk individuals to the development of CCA.

“In conclusion, our study provides a comprehensive analysis of diagnostic, prognostic, and therapeutic aspects of the complex CCA landscape,” commented Dr. Banales. “The results showed that CCA is mostly diagnosed at an advanced stage, a significant proportion of patients fail to receive any cancer-specific therapy, and the prognosis is dismal. Therapeutic options are limited. Accordingly, awareness campaigns and education programs aimed to prevent lifestyle-related risk factors and new techniques for early detection of CCA in high-risk populations are urgently needed in order to decrease cancer-related mortality. Our findings represent valuable knowledge for future comparisons with new targeted therapies and the design of next-generation personalized clinical trials.”

CCA is a highly heterogenous and aggressive malignancy responsible for around 2% of all cancer-related deaths globally each year. It is often diagnosed when it is already advanced, making it difficult to treat successfully. Currently it represents approximately 15% of all primary liver cancers and 3% of all gastrointestinal cancers worldwide.

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A study in the journal Science Immunology now shows how two subsets of one type of immune cell — the CD8 T cell — develop to provide either short-term or long-term immune protection. The study focuses on one factor that guides that developmental bifurcation — interleukin-2, or IL-2.

Understanding details of how naïve immune cells develop into effective infection-fighters or long-lived memory cells is important because it can help us understand which constituents of a complex response are necessary to provide protection against infections or cancers. It can also aid understanding of immune system dysfunction, or it can improve immunotherapy for cancer. Dysfunctions include autoimmune diseases, where the immune system attacks the body’s own cells, and exhaustion, where the immune system loses its ability to fight off continuing infection or the ability to destroy a cancer.

Study senior author Allan Zajac, Ph.D., and co-first authors Shannon M. Kahan, Ph.D., and Rakesh K. Bakshi, Ph.D., all of the University of Alabama at Birmingham Department of Microbiology, used mouse models to follow the traits and fates of the two subsets of CD8 T cells, starting from the peak of their effector phase, eight days after an acute viral infection.

CD8 T cells are a type of white blood cell that has the ability to develop into effector T cells — also known as cytotoxic T cells or killer T cells. These cells can destroy cancer cells or cells infected with viruses or bacteria. IL-2 is a cytokine, one of a large family of small signaling proteins that are released by cells to send messages to other cells, or act as an autocrine signal to the same cell that is making the cytokine. Cells receive the signal at the cell surface, where the cytokine binds to a receptor. The receptor transduces the signal to the cell interior, leading to changes in cell gene expression and phenotype.

Zajac and UAB colleagues were able to isolate and purify CD8 T cells from mice at the effector phase peak. Using fluorescence-activated cell sorting after cell stimulation with a viral antigen, they identified two subsets of this group — a minority of the CD8 T cells that produced IL-2 and a majority that did not produce IL-2.

The two subsets turn out to be strikingly different in the short term, in terms of developmental transitions that lead to fate decisions. However, they then become more alike months later.

The cells that produced IL-2 developed like immune memory cells. They attained stem-like memory traits, resisted exhaustion and preferentially conferred protective immunity upon a secondary viral challenge. Counterintuitively, they did not respond to their own IL-2, which acts inside the cell through a complex called STAT5, or signal transducer and activator of transcription. Even though the IL-2-producing CD8 T cells had normal amounts of IL-2 receptor proteins on the cell surface, the level of phosphorylated-STAT5 inside the cell — which is the activated form of STAT5 — was greatly diminished. The researchers hypothesized several mechanisms acting inside the cell possibly acting to attenuate the ability to receive IL-2-dependent STAT5 signals, but the answer is not yet known.

In contrast to the IL-2-producing cells, the non-IL-2-producing effector cells did respond to IL-2 signals, and they then gained effector traits at the expense of memory formation.

The UAB researchers did RNA sequencing of the cell subsets during the effector phase, nine days after infection, and much later, during the memory phase, about 10 months after infection. The transcriptional profiles of the IL-2-producing and the IL-2-non-producing effector populations were unique and distinguishable from their memory counterparts. However, by the memory time point, the two populations were more related to each other in gene expression. Thus, despite having distinct properties during the effector phase, the IL-2-producing and ?nonproducing CD8 T cells appeared to converge as memory matured to form populations with equal recall abilities to respond to a second viral infection or chronic viral challenge.

“This bifurcation between the ability of IL-2-producing and -nonproducing CD8 T cells to respond to IL-2 couples functional competency with fate decisions, and it implicates IL-2 as a critical differentiation factor,” Zajac said. Zajac notes that the salient findings of this study have not yet been confirmed for humans, and they are restricted to analyzing CD8 T cell responses to a single pathogen.

Co-authors with Zajac, Kahan and Bakshi in the study, “Intrinsic IL-2 production by effector CD8 T cells affects IL-2 signaling and promotes fate decisions, stemness, and protection,” are Jennifer T. Ingram, R. Curtis Hendrickson and Elliot J. Lefkowitz, UAB Department of Microbiology; David K. Crossman, UAB Department of Genetics; Laurie E. Harrington, UAB Department of Cell, Developmental and Integrative Biology; and Casey T. Weaver, UAB Department of Pathology. These UAB departments are all part of the Marnix E. Heersink School of Medicine.

Support came from National Institutes of Health grants AI049360, AI156290 and TR003096; and the American Cancer Society award PF-16-150-01-LIB. Zajac is a professor in the Department of Microbiology.

Out today in Environmental Research Letters, the new study finds that a subset of climate scenarios from the Intergovernmental Panel on Climate Change (IPCC) most in line with recent data and International Energy Agency (IEA) forecasts to 2050 project between 3.6 and 5.4 degrees F (2 and 3 C) of warming by 2100, with a median of 3.96 F (2.2 C) degrees. In comparison, some implausible, worst-case scenarios have projected as much as 7.2 or 9 F (4 or 5 C) degrees of warming by the end of the century.

“This is cautiously optimistic good news with respect to where the world is today, compared to where we thought we might be,” said lead author Roger Pielke Jr., professor of environmental studies. “The two-degree target from Paris remains within reach.”

In order to explore and plan for possible futures, the climate research community uses scenarios: forecasts of how the future might evolve based on factors such as projected greenhouse gas emissions and different possible climate policies.

The most commonly used scenarios, called the Representative Concentration Pathways (RCPs), were developed by the IPCC starting in 2005. The Shared Socioeconomic Pathways (SSPs) that followed, starting in 2010, were meant as an update. Together, the two sets of scenarios inform the IPCC’s Fifth and forthcoming Sixth Assessment Reports.

For their study, Pielke Jr. and his co-authors started with a total of 1,311 climate scenarios from which the climate research community selected the 11 RCPs and SSPs. Pielke and colleagues compared the scenarios to the projected 2005-2050 fossil fuel and industry carbon dioxide emissions growth rates most consistent with real-life observations from 2005-2020, and IEA projections to 2050. The number of scenarios which most closely matched up to data from the past 15 years and subsequent emissions projections ranged from less than 100 to almost 500, depending upon the method applied. These scenarios represent what futures are plausible if current trends continue and countries adopt the climate policies they have already announced to reduce carbon emissions.

Additional, more optimistic or pessimistic futures could also exist, the authors said.

“Because we haven’t updated our [IPCC] scenarios [for many years], there are also some futures which are plausible but haven’t yet been envisioned,” said Pielke Jr.

Pathways and plausibility

The analysis joins a growing consensus of independent groups around the world whose work finds that the most extreme climate scenarios are unlikely to occur this century, and mid-range scenarios are more likely. A report from the IPCC Sixth Assessment Report (AR6) released in 2021 also notes that the likelihood of high emissions scenarios is considered low.

Why are these worst-case scenarios now less plausible? Mainly, they were all developed more than a decade ago, and a lot has happened since.

For example, renewable energy has become more affordable and, thus, more common faster than expected, said Matthew Burgess, co-author and fellow in the Cooperative Institute for Research in Environmental Sciences (CIRES) at CU Boulder.

These fast-moving changes are captured in the scenarios drafted by the IEA, a Paris-based intergovernmental organization, which provides updates each year.

Climate scenarios also tend to overestimate economic growth, especially in poorer countries, according to Burgess, assistant professor of environmental studies.

In addition, while the 2010 scenarios were supposed to serve as updates to the socio-economic assumptions of the initial RCPs, the RCPs have continued to be used heavily by scientists. And the commonly used “worst-case” scenario, RCP8.5 (named for 8.5 watts per meter squared, a measure of solar irradiance) projects an increase of 7.2 to 9 F (4 to 5 C) by 2100.

“It’s hard to overstate how much the [climate] research has focused on the four- and five- degree scenarios, RCP 8.5 being one of them. And those are looking less and less plausible by the year,” said Burgess.

Relying on not only outdated scenarios, but scenarios which are no longer plausible, for research and policy has big implications for how we think about, act and spend money on climate change issues, the authors said.

“There’s a need for these scenarios to be updated more frequently. Researchers may be using a 2005 scenario, but we need a 2022 perspective,” said Pielke Jr. “You’re going to have better policies if you have a more accurate understanding of the problem, whatever the political implications are for one side or the other.”

The authors stress that 3.6 degrees F (2 C) of warming will still take a dramatic toll on the planet, and this is no time for complacency.

“We’re getting close to our two-degree target, but we definitely have a lot more work to do if we’re going to get to 1.5,” said Burgess.