Nav: Home

Nixing the cells that nix immune response against cancer

February 02, 2017

Some cells excite the immune system. Others soothe it. Myeloid-derived suppressor cells (MDSCs) are one type of soothing cell, and previous work shows that cancer may specifically boost production of MDSCs as a way to tamp down immune response against tumors. At least that's how it works in mice. Now a University of Colorado Cancer Center study published in the journal Cancer Immunology & Immunotherapy for the first time characterizes the uptick of these cells in the spleens of human cancer patients, paving the way for therapies directed against these suppressor cells that collude with cancer.

"I would estimate that the majority of basic immunology has been worked out in mice, specifically in the spleens of mice because they offer ready access to large numbers of lymphocytes or splenocytes. Many versions of vaccines and tumor models rely on the responses of these mouse splenocytes. But it turns out we don't know as much about human splenocytes and their immunologic importance. There's a big leap of faith that mouse models are applicable to humans," says Martin McCarter, MD, investigator at the University of Colorado Cancer Center and surgical oncologist at the University of Colorado Hospital.

In fact, when McCarter, first author Kim Jordan, PhD, and colleagues examined the spleens of 26 patients with a variety of cancers, they found important differences between human and mouse splenocytes. First, whereas mouse splenocytes are plentiful, human splenocytes are less abundant. Second, while mouse splenocytes are easy to isolate, human splenocytes may include a complex mix of markers, making them more difficult to separate from the many other kinds of cells found in the spleen.

"Basically, this means that it's really easy to find and study these splenocytes in mice and really hard to get your hands on enough human splenocytes to study," says Jordan, who is assistant director of the CU Cancer Center Human Immune Monitoring Shared Resource and assistant research professor in the CU School of Medicine Department of Immunology and Microbiology. "Now with this paper we show how future researchers can isolate these human splenocytes, hopefully leading to more work in this area."

However, when the team compared these spleens from cancer patients to spleens from patients with benign pancreatic cysts, they found an important similarity with existing mouse models: Splenocytes were indeed more prevalent in cancer patients than in the non-cancer control group.

The team went an important step beyond characterizing and isolating these cells: "It's one thing to identify these cells and another to show their function," McCarter says. "We show that these cells are functionally immunosuppressive in humans, working to block T-cell responses."

When increased splenocytes blocked T-cell responses, patients suffered - in this study, higher splenocyte counts were "associated with a significantly increased risk of death and decreased overall survival," the authors discovered.

Many successful anti-cancer immunotherapies direct T cells to target tumors. For example, PD-1 and PD-L1 inhibitors prevent tumor cells from holding up a sort of biological "white flag" that disarms T cells that would otherwise target them. Another immunologic strategy called CAR-T cell therapy seeks to genetically equip T cells to recognize proteins specific to tumor tissue. Both therapies depend on T cell responses. And in both cases, a tumor's ability to spur the growth of myeloid-derived suppressor cells may blunt this response.

"In recent years, we've started to crack open the shell of the immune response to tumors. Still, there are many elements of the immune system we don't understand, for example how tumors manipulate or utilize a patient's own immune system to block the immune response against their own tissue. Now we are taking steps to understand this process, and understanding the basic science allows us the opportunity to intervene with therapies to stop it," McCarter says.

The group has already taken the obvious next step, running an investigator-initiated human clinical trial targeting myeloid-derived suppressor cells in combination with existing immunotherapies in a way that could allow immune response to go forward. McCarter, Jordan and colleagues are excited to report the results of this small trial in a forthcoming publication.

"Currently only about 20-40 percent of melanoma patients respond to these immune therapy checkpoint inhibitors for a variable amount of time," McCarter says. "By blocking or knocking down the myeloid-derived suppressor cells, we hope to improve this response rate."

University of Colorado Anschutz Medical Campus

Related Cancer Articles:

Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Cancer genomics continued: Triple negative breast cancer and cancer immunotherapy
Continuing PLOS Medicine's special issue on cancer genomics, Christos Hatzis of Yale University, New Haven, Conn., USA and colleagues describe a new subtype of triple negative breast cancer that may be more amenable to treatment than other cases of this difficult-to-treat disease.
Metabolite that promotes cancer cell transformation and colorectal cancer spread identified
Osaka University researchers revealed that the metabolite D-2-hydroxyglurate (D-2HG) promotes epithelial-mesenchymal transition of colorectal cancer cells, leading them to develop features of lower adherence to neighboring cells, increased invasiveness, and greater likelihood of metastatic spread.
UH Cancer Center researcher finds new driver of an aggressive form of brain cancer
University of Hawai'i Cancer Center researchers have identified an essential driver of tumor cell invasion in glioblastoma, the most aggressive form of brain cancer that can occur at any age.
UH Cancer Center researchers develop algorithm to find precise cancer treatments
University of Hawai'i Cancer Center researchers developed a computational algorithm to analyze 'Big Data' obtained from tumor samples to better understand and treat cancer.
More Cancer News and Cancer Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Teaching For Better Humans
More than test scores or good grades — what do kids need to prepare them for the future? This hour, guest host Manoush Zomorodi and TED speakers explore how to help children grow into better humans, in and out of the classroom. Guests include educators Olympia Della Flora and Liz Kleinrock, psychologist Thomas Curran, and writer Jacqueline Woodson.
Now Playing: Science for the People

#535 Superior
Apologies for the delay getting this week's episode out! A technical glitch slowed us down, but all is once again well. This week, we look at the often troubling intertwining of science and race: its long history, its ability to persist even during periods of disrepute, and the current forms it takes as it resurfaces, leveraging the internet and nationalism to buoy itself. We speak with Angela Saini, independent journalist and author of the new book "Superior: The Return of Race Science", about where race science went and how it's coming back.