Breaking News
January 17, 2019 - Researchers demonstrate how manganese produces parkinsonian syndrome
January 17, 2019 - Researchers suggest link between personality type and attitude towards others’ bodies
January 17, 2019 - Mutant mice administered with cocaine failed to exhibit hyperactivity, shows study
January 17, 2019 - Health Tip: Understanding a Heart Murmur
January 17, 2019 - Gut protein mutations shield against spikes in glucose
January 17, 2019 - Engineered immune cells target broad range of pediatric solid tumors in mice | News Center
January 17, 2019 - Study finds link between high pesticide exposure and poor sense of smell among farmers
January 17, 2019 - New study finds only 13% of outpatient antibiotic prescriptions to be appropriate
January 17, 2019 - New project receives €8.65 million from EU and Canada to ease genomic, health data sharing
January 17, 2019 - Improvements in pharmacological study to fight cognitive impairment in schizophrenia
January 17, 2019 - Study looks at trends over time in oral antibiotic prescribing by dermatologists
January 17, 2019 - Most substance use disorder treatment facilities do not offer medication treatment
January 17, 2019 - Multiple sclerosis could benefit from stem cell therapy
January 17, 2019 - Researchers manipulate T cells to improve transplant success
January 17, 2019 - Put away your rulers and reach for your phone
January 17, 2019 - Integrated care to women with PMADs offered at several levels
January 17, 2019 - Researchers identify MANF as a rejuvenating factor in parabiosis
January 17, 2019 - Truncal mutations study suggests new direction in origins of cancer
January 17, 2019 - Beckman Coulter launches new ClearLLab 10C System for clinical flow cytometry lab
January 17, 2019 - Effects of linoleic acid on the body are largely dependent on genes, shows study
January 17, 2019 - Pre-injury exercise reduces damage to both muscles and nerves, study finds
January 17, 2019 - Minimizing Antibody Size to Maximize Research Potential
January 17, 2019 - Research finds large genome in tiny forest defoliator
January 17, 2019 - Technology helps reduce the yearning for unhealthy food
January 17, 2019 - Imec develops prototype cardiovascular device
January 17, 2019 - New Drug Application for Insomnia Disorder Treatment Lemborexant Submitted in the United States
January 17, 2019 - What you should know about teeth whitening
January 17, 2019 - Why Older Adults Should Eat More Protein (And Not Overdo Protein Shakes)
January 17, 2019 - Colorectal cancer mortality rates predicted to increase globally
January 17, 2019 - Scientists discover mutational signatures of tumor hypoxia
January 17, 2019 - New evidence shows how fever alters immune cells
January 17, 2019 - Researchers find new class of blood pressure-regulating peptides in vampire bat venom
January 17, 2019 - Promega to exhibit new Maxwell RSC48 platform at 2019 Festival of Genomics
January 17, 2019 - Study pinpoints immune cells that could be key to tackling hypertension
January 17, 2019 - Couples Intervention May Aid Partners of Diabetes Patients
January 17, 2019 - Your weight history may predict your heart failure risk
January 17, 2019 - Explore a cornucopia of accomplishments in prematurity research
January 17, 2019 - New study identifies four characteristics that predict severity of postpartum depression
January 17, 2019 - AHF urges United Nations to follow own mandate for protecting Ebola response efforts
January 17, 2019 - New, scalpel-free treatment for reducing Parkinson’s tremor gets FDA approval
January 17, 2019 - Neurobiologists uncover key component of how the human brain marks time
January 17, 2019 - LifeTime receives fund to develop a plan to embed its vision for healthier future
January 17, 2019 - WTC first responders at higher risk for head and neck cancers, study finds
January 17, 2019 - New NSF funded study may help physicians decrease brain injury deaths
January 17, 2019 - Ham bones contain peptides that could have cardioprotective effects
January 17, 2019 - Research finds how Candida albicans adapt to low oxygen levels to cause infection
January 17, 2019 - Cobra Biologics announces appointment of Dr Darrell Sleep as Director of Innovation
January 17, 2019 - Cellular protein that interacts with viruses appears to enable infection process of Zika virus
January 17, 2019 - Opioids Now More Deadly for Americans Than Traffic Accidents
January 17, 2019 - Women who start periods early are at greater risk of cardiovascular problems
January 17, 2019 - The brain-circuitry clash that keeps you from diving into that plate of ribs when you’re dining with royalty
January 17, 2019 - Poo transplant can successfully treat patients with ulcerative colitis
January 17, 2019 - Study suggests key role for glial cells in Parkinson’s disease
January 17, 2019 - Educational videos in clinical settings increase HPV vaccination rates among adolescents
January 17, 2019 - Better understanding of aggressive brain tumour
January 17, 2019 - Why is life expectancy in the U.S. going down? A Q&A
January 17, 2019 - The Electronics Industry Sees Money In Your Health
January 17, 2019 - Hypertension drug may improve effectiveness of ovarian cancer treatment
January 17, 2019 - Scientists reveal key mechanism in worms that controls cell’s response to stress
January 17, 2019 - How Patch Clamp Technology Can Benefit Ion Channel Research
January 16, 2019 - Researchers cultivate organoids that perfectly mimic blood vessels
January 16, 2019 - Sound Pharmaceuticals Advances Phase 2 Hearing Loss Clinical Trial in Cystic Fibrosis
January 16, 2019 - Unraveling the genetic causes of skin cancer
January 16, 2019 - Higher percentages of saturated fat in low-carb diets may not harm cholesterol levels, new analysis suggests
January 16, 2019 - Using bottled or tap water impacts health benefits of green tea
January 16, 2019 - Best trained alert dogs have potential to improve Type 1 diabetes patients’ quality of life
January 16, 2019 - States with lower incidence of melanoma have higher mortality rates
January 16, 2019 - Pollution on the London Underground found to be dangerously high
January 16, 2019 - Breast cancer cells in mice coaxed to turn into harmless fat cells
January 16, 2019 - Study connects the genetic background of autistic spectrum disorders with stem cell dysfunction
January 16, 2019 - When activated, ‘social’ brain circuits inhibit feeding behavior in mice | News Center
January 16, 2019 - How Exercise May Help Keep Our Memory Sharp
January 16, 2019 - Researchers identify a key regulator that stops excessive inflammation
January 16, 2019 - TGF-beta signaling pathway in uterine cells protects against cancer
January 16, 2019 - MD Anderson Cancer Center collaborates with Dragonfly for new immunotherapy drug clinical trials
January 16, 2019 - Drug Repurposing May Provide More Psychiatric Tx Options
January 16, 2019 - A new brain imaging study challenges the dominant theoretical model of autism spectrum disorders
January 16, 2019 - GoFundMe CEO: ‘Gigantic Gaps’ In Health System Showing Up In Crowdfunding
January 16, 2019 - Induced neuronal cells derived from fibroblasts are similar to neurons in the brain
January 16, 2019 - New study finds link between childhood abuse and suicide in later life
New potential immunotherapy target in pancreatic cancer identified

New potential immunotherapy target in pancreatic cancer identified

image_pdfDownload PDFimage_print

Researchers have identified a new potential immunotherapy target in pancreatic cancer, which so far has been notoriously resistant to treatment with immune checkpoint blockade drugs effective against a variety of other cancers.

The University of Texas MD Anderson Cancer Center research team found overexpression of the immune checkpoint VISTA on immune cells, especially macrophages, that infiltrated pancreatic tumors. Their paper will be published online Friday at the Proceedings of the National Academy of Sciences.

“VISTA is a potential therapeutic target in pancreatic cancer, and there are several antibodies to block VISTA under clinical development,” said co-senior author Padmanee Sharma, M.D., Ph.D., professor of Genitourinary Medical Oncology and Immunology. “Additional research also needs to be done to see if we can come up with other targets for these VISTA-positive cells as well.”

Present immune checkpoint inhibitors that unleash an immune attack on cancer by blocking PD-1 and CTLA-4 brakes on T cells have been ineffective against pancreatic cancer, one of the most lethal cancers. The five-year survival rate for patients with pancreatic cancer is 7 percent or less.

The team, led by Sharma and 2018 Nobel Laureate Jim Allison, Ph.D., professor and chair of Immunology, set out to shed light on infiltration of immune cells and expression of immunity-inhibiting checkpoints in pancreatic cancer by comparing those tumors to melanoma, the cancer that is most vulnerable to immune checkpoint blockade.

They first analyzed expression of nine immune inhibitory genes in 23 untreated, surgically removed pancreatic cancer tumors and found the results separated the patients into two groups, 11 with high-expression of inhibitory genes and 12 with low expression.

Those with low-expression of immune inhibitors had a median survival of 37 months versus 20 months for the high-expression group, indicating potential immune impact on overall survival.

Tumor architecture: Stroma and malignant cells

Pancreatic cancer tumors include a high density of stroma, non-malignant supportive cells, while melanoma is at the other end of the spectrum with minimal stroma. These differences came into play in the team’s analyses. The pancreatic tumors were composed of 30 percent malignant cells and 70 percent stroma, while those proportions were flipped in melanoma tumors.

In addition to the vastly different ratio of stromal cells, the architecture of the tumor types also diverges, Sharma notes. “In melanoma, you have a large area of malignant cells surrounded by a thin layer of stroma. With pancreatic cancer, it’s more like cancer cells, stroma, cancer cells, stroma ? blended.”

Analysis of 29 untreated pancreatic cancer tumors and 44 untreated melanomas found heavier penetration of attacking immune T cells in melanoma as well as higher levels of cells expressing the inhibitory checkpoint molecules PD-1 and its activating ligand PD-L1, which are successfully targeted by inhibitors to treat melanoma. However, pancreatic tumors had much higher expression of VISTA.

About a third of the pancreatic tumors had T cell penetration roughly equal to that found in melanoma, but the T cells were concentrated mainly in the stroma of the tumors, rather than the malignant cells, while they were evenly distributed between cancer cells and stroma in melanoma.

To the researchers, that makes sense. “In pancreatic cancer, you have much more stroma than malignant cells in the tumor. Why is that? I think it’s how the tumor is growing,” Sharma said.

Allison noted the stromal cells might be keeping the T cells out of the cancer cells.

VISTA and macrophages

VISTA is predominantly expressed on macrophages – “big eater” immune cells that engulf and digest microbes, cellular debris, and tumor cells as part of immune response. VISTA is known to deactivate T cells.

While the researchers found roughly equal density of CD68-positive macrophages in both tumor types, in pancreatic cancer they were again concentrated in the stroma. Macrophages in the pancreatic tumors had much higher expression of VISTA.

A separate comparison of three types of pancreatic tumor – untreated primary, treated metastatic and primary tumors pretreated before surgery – found low penetration of T cells in the metastatic tumors and elevated levels of VISTA in the untreated primary and metastatic tumors.

Analysis of seven pancreatic samples found that CD68-positive macrophages had distinct PD-L1 and VISTA pathways that inhibit immune response separately. Experiments with T cells taken from tumors of three patients with metastatic pancreatic cancer showed that an active VISTA pathway decreased active T cell responses in the tumor to a greater degree than PD-L1 inhibition. This suggests treatment with PD-1/PD-L1 inhibition might fail because an untreated VISTA pathway still suppresses immune response.

Moon Shots Program collaboration

Future research will include exploration of combination therapy strategies to increase T cell infiltration, possibly using anti-CTLA-4 checkpoint inhibition, plus a VISTA antibody to target macrophages, Sharma said.

Allison and Sharma lead MD Anderson’s immunotherapy platform, which thoroughly characterizes immune response to tumors and to treatment via immune monitoring of tumor samples before, during and after treatment. The platform team worked with MD Anderson’s Pancreatic Cancer Moon Shot™ and Melanoma Moon Shot™, part of the institution’s Moon Shots Program™, a collaborative effort to accelerate the development of scientific discoveries into clinical advances that save patients’ lives.

Source:

https://www.mdanderson.org/newsroom/vista-checkpoint-implicated-in-pancreatic-cancer-immunotherapy-resistance.h00-159299889.html

Tagged with:

About author

Related Articles