Nav: Home

Molecular chatter makes for a 'hot tumor'

June 10, 2019

JUNE 10, 2019, NEW YORK - A Ludwig Cancer Research study has deciphered a complex molecular conversation between cancer and immune cells that is key to orchestrating the successful invasion of tumors by T cells that kill cancer cells.

"We show that two key chemokines, CCL5 and CXCL9, are universally implicated in T cell infiltration across all solid tumors," said George Coukos, who directs the Lausanne Branch of the Ludwig Institute for Cancer Research and led the study. "Their simultaneous presence in tumors is a key requirement for the engraftment of T cells and the establishment of a T cell-inflamed tumor, also known as a 'hot tumor.'"

Chemokines, signaling proteins that mediate the traffic of various immune cells into the tumor microenvironment, help T-cells home in on tumors and can affect tumor immunity and therapeutic outcomes. But which chemokines are involved and how they interact with one another to that end was not well understood.

The study, published in the current issue of the journal Cancer Cell, identifies biomarkers of great relevance to cancer immunotherapy and could enable a more precise clinical classification of tumors. It could also inform the design of new kinds of cell based and other immunotherapies for cancer. "These findings have advanced our understanding of how the T cell attack on tumors is orchestrated naturally in T cell-inflamed tumors," said Denarda Dangaj, a postdoctoral researcher at Ludwig Lausanne who is first author of the paper.

This latest research was prompted by the Coukos lab's 2003 discovery that ovarian cancer patients whose tumors are infiltrated by killer (or CD8+) T cells--which destroy infected and cancerous cells--demonstrate improved survival. Other studies have found similar correlations in most solid tumors.

In the current study, Coukos and his team identified two chemokines, CCL5 and CXCL9, that are consistently associated with CD8+ T cell infiltration of solid tumors. They show that CCL5 is expressed by cancer cells, while CXCL9 is produced by other (so-called myeloid) immune cells known as macrophages and dendritic cells that are also present in the tumor. When cancer cells drop their production of CCL5, CXCL9 expression drops as well. This results in the progressive depletion of CD8+ T cells in tumors.

This loss of CCL5 expression in cancer cells, they found, correlates with a chemical modification to DNA that suppresses the expression of targeted genes--a mechanism known as epigenetic silencing. The researchers suggest the epigenetic silencing of CCL5 is an adaptive mechanism by which tumors escape immune attack.

Cancer cells have good reason to suppress CCL5: it attracts CD8+ T cells. The researchers show that when T cells drawn by CCL5 reach the tumor and are activated by cancer antigens, they release a signaling protein of their own called interferon gamma (IFNγ). This, they discovered, causes macrophages and dendritic cells that have congregated at the tumor to secrete CXCL9, which dramatically boosts the infiltration of the tumor by circulating T cells.

"CCL5 is the key chemokine determining whether a tumor will be T cell inflamed," Coukos said. "However, CCL5 expression alone is not sufficient, and CXCL9 is a major amplifier of T cell recruitment."

These findings suggest CCL5 and CXCL9 could be useful biomarkers for immunotherapy. Most notably, they could help identify patients whose tumors are infiltrated by activated T cells and are therefore more likely to be susceptible to immunotherapies like anti-PD1 antibodies.

The newly discovered mechanism of immune evasion too might be exploited for therapy. "Knowing that CCL5 silencing is reversible by the drug decitabine provides a strong rationale to combine that epigenetic therapy with PD1 blockade," says Coukos.
-end-
This research was supported by Ludwig Cancer Research, SPORE in Ovarian Cancer, the Sidney Kimmel Foundation, the Emma Mouschamp Foundation and the Swiss Medic Foundation. Aside from his Ludwig post, George Coukos is director of the Department of Oncology at the University Hospital of Lausanne (CHUV-UNIL) and co-director of the Swiss Cancer Center, Léman.

About Ludwig Cancer Research

Ludwig Cancer Research is an international collaborative network of acclaimed scientists that has pioneered cancer research and landmark discovery for more than 40 years. Ludwig combines basic science with the ability to translate its discoveries and conduct clinical trials to accelerate the development of new cancer diagnostics and therapies. Since 1971, Ludwig has invested $2.7 billion in life-changing science through the not-for-profit Ludwig Institute for Cancer Research and the six U.S.-based Ludwig Centers. To learn more, visit http://www.ludwigcancerresearch.org.

For further information please contact Rachel Reinhardt, rreinhardt@lcr.org or +1-212-450-1582.

Ludwig Institute for Cancer Research

Related Cancer Articles:

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.
Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.
Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.
Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.
More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.
New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.
American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.
Oncotarget: Cancer pioneer employs physics to approach cancer in last research article
In the cover article of Tuesday's issue of Oncotarget, James Frost, MD, PhD, Kenneth Pienta, MD, and the late Donald Coffey, Ph.D., use a theory of physical and biophysical symmetry to derive a new conceptualization of cancer.
Health indicators for newborns of breast cancer survivors may vary by cancer type
In a study published in the International Journal of Cancer, researchers from the UNC Lineberger Comprehensive Cancer Center analyzed health indicators for children born to young breast cancer survivors in North Carolina.
Few women with history of breast cancer and ovarian cancer take a recommended genetic test
More than 80 percent of women living with a history of breast or ovarian cancer at high-risk of having a gene mutation have never taken the test that can detect it.
More Cancer News and Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Uncharted
There's so much we've yet to explore–from outer space to the deep ocean to our own brains. This hour, Manoush goes on a journey through those uncharted places, led by TED Science Curator David Biello.
Now Playing: Science for the People

#556 The Power of Friendship
It's 2020 and times are tough. Maybe some of us are learning about social distancing the hard way. Maybe we just are all a little anxious. No matter what, we could probably use a friend. But what is a friend, exactly? And why do we need them so much? This week host Bethany Brookshire speaks with Lydia Denworth, author of the new book "Friendship: The Evolution, Biology, and Extraordinary Power of Life's Fundamental Bond". This episode is hosted by Bethany Brookshire, science writer from Science News.
Now Playing: Radiolab

Dispatch 2: Every Day is Ignaz Semmelweis Day
It began with a tweet: "EVERY DAY IS IGNAZ SEMMELWEIS DAY." Carl Zimmer – tweet author, acclaimed science writer and friend of the show – tells the story of a mysterious, deadly illness that struck 19th century Vienna, and the ill-fated hero who uncovered its cure ... and gave us our best weapon (so far) against the current global pandemic. This episode was reported and produced with help from Bethel Habte and Latif Nasser. Support Radiolab today at Radiolab.org/donate.