Nav: Home

Double agents: Vessels that help cancers spread can also boost immunotherapy

September 13, 2017

Many cancers, such as melanoma, are known to metastasize and spread by expanding nearby lymphatic vessels. This process, lymphangiogenesis, also helps the tumor evade the patient's own immune system, and it would be expected that inhibiting lymphangiogenesis, could enhance the efficacy of cancer immunotherapies, which are only effective in a minority of patients. But in a surprising discovery, scientists from EPFL and the US found the opposite: lymphangiogenesis actually enhances the effectiveness of immunotherapy against melanoma. Published in Science Translational Medicine, the study has significant implications for new types of cancer therapies.

Cancer immunotherapy is one of the most promising treatments against tumors. The process involves overcoming the tumor's suppression of immune attacks, thus allowing the patient's own immune system to destroy it. But despite the highly encouraging results from clinics only a subset of patients is able to respond to immunotherapy. Until now, the reasons have been unclear.

One of the problems is that many tumors evolve clever defenses against the patient's immune system to evade or survive such attacks. For example, melanomas and other tumors induce lymphangiogenesis with a protein called Vascular Endothelial Growth Factor C (VEGF-C). The presence of VEGF-C and subsequent lymphangiogenesis are generally signs of metastasis and create a poor prognosis for the patient. In addition, recent studies have also suggested that VEGF-C may also help the melanoma tumor suppress the patient's immune system.

Consequently, a team of scientists led by the lab Melody Swartz at EPFL (now at the University of Chicago) with co-first authors Manuel Fankhauser and Maria Broggi hypothesized that VEGF-C induced lymphangiogenesis and immune suppression would hinder the effectiveness of immunotherapy.

Surprisingly, the scientists found that VEGF-C and lymphangiogenesis can strongly boost the effects of immunotherapy in melanoma. The discovery was unexpected, as the scientists were trying to enhance immunotherapy by blocking VEGF-C in mouse melanoma models. Instead, they observed the opposite: the impact of immunotherapy on mice with melanoma actually got worse when lymphangiogenesis was blocked.

Following up with further studies, the researchers found an explanation for their observations: the new lymphatic vessels created by the melanoma tumor secrete the chemokine CCL21, which actively attracts naïve (undifferentiated) T cells into the tumor's immunosuppressed microenvironment. Once in the tumor, these naïve T cells are locally activated following immunotherapy-induced tumor cell death, which triggers a positive feedback loop of long-lasting anti-tumor immunity.

The team tested their hypothesis on different mouse models of melanoma using multiple immunotherapy approaches, including vaccination and adoptive T cell transfer. All of these eradicated or slowed down the growth of primary melanoma tumors, and in some settings even conferred the mice with long-term protection against metastasis.

Beyond the pre-clinical models though, the scientists tested their hypothesis in human patients with melanoma. "The difference was really striking," says Melody Swartz. "Almost all of the patients with higher than average VEGF-C levels in their blood responded to immunotherapy. This not only resulted in eradication of the primary tumors, it also encouraged T cell infiltration into metastatic tumors and resulted in long-term protection." The researchers therefore propose that VEGF-C can be a predictive biomarker that indicates how well a patient is responding to immunotherapy.

"We now appreciate the numerous mechanisms of immunosuppression that a T cell-inflamed tumor develops to survive, including lymphangiogenesis," the authors write. "But when the scales are tipped toward activating factors dominating over suppressive ones, as is the case with immunotherapy, these T cells become robust participants in antitumor immunity."

The findings reveal an unappreciated role of tumor-associated lymphangiogenesis in shaping the tumor's immune microenvironment, and pave the way for therapeutic strategies that exploit it. The study is of critical importance to cancer immunotherapy, which is growing into a formidable weapon against tumors of different types. For example, the FDA recently approved CAR-T cell therapy for leukemia and several checkpoint inhibitors are already approved for the treatment of solid tumors such as melanoma. All of these are breakthrough medicines that are now curing patients who would previously have had low chances for survival.
-end-
Contributing institutions
  • Institute for Molecular Engineering and The Ben May Institute for Cancer Research, University of Chicago

  • Department of Oncology and Ludwig Cancer Research, University of Lausanne

  • Oregon Health and Science University

  • Bioinformatics and Biostatistics Core Facility, EPFL

  • Swiss Institute for Experimental Cancer Research (ISREC), EPFL

Funding
  • Swiss National Science Foundation

  • Swiss TransMed

  • European Research Council (ERC)

  • Fonds Pierre-François Vittone

Reference

Manuel Fankhauser, Maria A.S. Broggi, Lambert Potin, Natacha Bordry, Laura Jeanbart, Amanda W. Lund, Elodie Da Costa, Sylvie Hauert, Marcela Rincon-Restrepo, Christopher Tremblay, Elena Cabello, Krisztian Homicsko, Olivier Michielin, Douglas Hanahan, Daniel E. Speiser, Melody A. Swartz. Tumor lymphangiogenesis promotes T cell infiltration and potentiates immunotherapy in melanoma. Science Translational Medicine 13 September 2017. DOI: 10.1126/scitranslmed.aal4712

Ecole Polytechnique Fédérale de Lausanne

Related Immune System Articles:

The immune system may explain skepticism towards immigrants
There is a strong correlation between our fear of infection and our skepticism towards immigrants.
New insights on how pathogens escape the immune system
The bacterium Salmonella enterica causes gastroenteritis in humans and is one of the leading causes of food-borne infectious diseases.
Understanding how HIV evades the immune system
Monash University (Australia) and Cardiff University (UK) researchers have come a step further in understanding how the human immunodeficiency virus (HIV) evades the immune system.
Carbs during workouts help immune system recovery
Eating carbohydrates during intense exercise helps to minimise exercise-induced immune disturbances and can aid the body's recovery, QUT research has found.
A new model for activation of the immune system
By studying a large protein (the C1 protein) with X-rays and electron microscopy, researchers from Aarhus University in Denmark have established a new model for how an important part of the innate immune system is activated.
Guards of the human immune system unraveled
Dendritic cells represent an important component of the immune system: they recognize and engulf invaders, which subsequently triggers a pathogen-specific immune response.
How our immune system targets TB
Researchers have seen, for the very first time, how the human immune system recognizes tuberculosis (TB).
How a fungus inhibits the immune system of plants
A newly discovered protein from a fungus is able to suppress the innate immune system of plants.
A new view of the immune system
Pathogen epitopes are fragments of bacterial or viral proteins. Nearly a third of all existing human epitopes consist of two different fragments.
TB tricks the body's immune system to allow it to spread
Tuberculosis tricks the immune system into attacking the body's lung tissue so the bacteria are allowed to spread to other people, new research from the University of Southampton suggests.

Related Immune System Reading:

How the Immune System Works (The How it Works Series)
by Lauren M. Sompayrac (Author)

How the Immune System Works has helped thousands of students understand what’s in their big, thick, immunology textbooks. In his book, Dr. Sompayrac cuts through the jargon and details to reveal, in simple language, the essence of this complex subject.

In fifteen easy-to-read chapters, featuring the humorous style and engaging analogies developed by Dr. Sompayrac, How the Immune System Works explains how the immune system players work together to protect us from disease – and, most importantly, why they do it this way.

Rigorously updated for this fifth... View Details


The Immune System Recovery Plan: A Doctor's 4-Step Program to Treat Autoimmune Disease
by Susan Blum (Author), Mark Hyman (Foreword), Michele Bender (Foreword)

One of the most sought-after experts in the field of functional medicine shares her proven four-step program to treat, reverse, and prevent autoimmune conditions and repair your immune system.

• Are you constantly exhausted?

• Do you frequently feel sick?

• Are you hot when others are cold, or cold when everyone else is warm?

• Do you have trouble thinking clearly, aka “brain fog”?

• Do you often feel irritable?

• Are you experiencing hair loss, dry skin, or unexplained weight fluctuation?

• Do your joints ache or... View Details


The Immune System, 4th Edition
by Peter Parham (Author)

The Immune System, Fourth Edition emphasizes the human immune system and presents immunological concepts in a coherent, concise, and contemporary account of how the immune system works. Written for undergraduate, medical, veterinary, dental, and pharmacy students, it makes generous use of medical examples to illustrate points. This classroom-proven textbook offers clear writing, full-color illustrations, and section and chapter summaries that make the book accessible and easily understandable to students.

The Fourth Edition is a major revision that brings the content... View Details


The Immune System, 3rd Edition
by Peter Parham (Author)

The Immune System, Third Edition emphasizes the human immune system and synthesizes immunological concepts into a comprehensible, up-to-date, and reader-friendly account of how the immune system works. 

Written for undergraduate, medical, veterinary, dental, and pharmacy students in immunology courses, it makes generous use of medical examples to illustrate points. 

The Third Edition has been extensively revised and updated and includes two new chapters on innate and adaptive immunity, which explore the physical, cellular, and molecular principles... View Details


Basic Immunology: Functions and Disorders of the Immune System, 5e
by Abul K. Abbas MBBS (Author), Andrew H. H. Lichtman MD PhD (Author), Shiv Pillai MBBS PhD (Author)

In this updated edition of Basic Immunology, the authors continue to deliver a clear, modern introduction to immunology, making this the obvious choice for today's busy students. Their experience as teachers, course directors, and lecturers helps them to distill the core information required to understand this complex field. Through the use of high-quality illustrations, relevant clinical cases, and concise, focused text, it's a perfectly accessible introduction to the workings of the human immune system, with an emphasis on clinical relevance.... View Details


The Immune System: A Dewey Decimal novel (Akashic Urban Surreal Series)
by Nathan Larson (Author)

"This final installment of the Dewey Decimal trilogy capably stands alone as a quirky, sparkly read that will embiggen your cerebellum."
--Library Journal

"Larson treats the English language as a sort of toy to play with and use for experimentation; language is not just used to tell the story, in other words, but is a part of the story, an extension of its narrator, Dewey Decimal, one of the more offbeat characters in fiction. A fitting conclusion to a unique and memorable trilogy."
--Booklist

"A sharp and satisfying conclusion to one of the... View Details


The Immune System: A Very Short Introduction (Very Short Introductions)
by Paul Klenerman (Author)

The immune system is central to human health and the focus of much medical research. Growing understanding of the immune system, and especially the creation of immune memory (long lasting protection), which can be harnessed in the design of vaccines, have been major breakthroughs in medicine.

In this Very Short Introduction, Paul Klenerman describes the immune system, and how it works in health and disease. In particular he focuses on the human immune system, considering how it evolved, the basic rules that govern its behavior, and the major health threats where it is... View Details


A Guide to Transfer Factors and Immune System Health: 2nd edition, Helping the body heal itself by strengthening cell-mediated immunity
by Aaron White PhD (Author)

In the second edition of this popular book, Dr. White takes readers on a tour of the human immune system, explores the nature of immune disorders from cancer to HIV and presents evidence that immune messengers called transfer factors can help the body beat a wide variety of diseases for which effective treatments are lacking. In language that is easy to follow, Dr. White explains how transfer factors help the body fight viruses (herpes, hepatitis C, HPV, HIV), mycobacteria (tuberculosis), cell-wall deficient bacteria (Lyme), cancers, autoimmune diseases and other conditions. Like vaccines but... View Details


The Immune System Cure: Optimize Your Immune System in 30 Days-The Natural Way!
by Lorna Vanderheaghe (Author)

What causes one person to catch a cold or flu and another to avoid it? Why do serious outbreaks of infectious diseases leave some individuals untouched? What allows someone to be incapacitated by allergies? The answer lies within nature itself-our immune system. The Immune System Cure provides simple techniques for supercharging your immune system to resist and prevent disease. Through diet, exercise, stress reduction and nutritional supplements, including plant sterols and sterolins, you can harness the power of your immune system in just 30 days and help it combat: Antibiotic-resistant... View Details


Immune System: 101 Natural Ways to Boost your Immune System, Fight Germs, and Live a Healthy Life
by Living in Health (Author)

BOOST YOUR IMMUNE SYSTEM! 101 NATURAL WAYS TO BOOST YOUR IMMUNE SYSTEM, FIGHT GERMS, AND LIVE A HEALTHY LIFE Your immune system is the body’s only line of defense against both foreign and internal threats. It is clear therefore that you must maintain your immune system in the best possible condition for optimal health. It is not a myth that some foods are better than others at boosting our immunity. If you were ever wondering what might be the best foods in the world to help keep your immune system in the best shape, then this book is simply the way to go. It really helps to have a great... View Details

Best Science Podcasts 2017

We have hand picked the best science podcasts for 2017. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Simple Solutions
Sometimes, the best solutions to complex problems are simple. But simple doesn't always mean easy. This hour, TED speakers describe the innovation and hard work that goes into achieving simplicity. Guests include designer Mileha Soneji, chef Sam Kass, sleep researcher Wendy Troxel, public health advocate Myriam Sidibe, and engineer Amos Winter.
Now Playing: Science for the People

#448 Pavlov (Rebroadcast)
This week, we're learning about the life and work of a groundbreaking physiologist whose work on learning and instinct is familiar worldwide, and almost universally misunderstood. We'll spend the hour with Daniel Todes, Ph.D, Professor of History of Medicine at The Johns Hopkins University, discussing his book "Ivan Pavlov: A Russian Life in Science."