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Tumor Cell-Derived IL-1[beta] Promotes Desmoplasia & Immune Suppression in Pancreatic Cancer

A key immune signal has a previously unknown role in turning off the immune system's attack on pancreatic cancer cells, a new study finds (Cancer Res 2020; doi: 10.1158/0008-5472.CAN-19-2080). Research found that an immune signaling protein, interleukin-1[beta] (IL-1[beta]), is made and released by pancreatic tumor cells. This was shown to reduce anti-cancer immune responses, which promoted the growth of pancreatic ductal adenocarcinoma (PDA), a form of cancer that is usually deadly within 2 years. The study also found that blocking the action of IL-1[beta] in mice with immune proteins caused a 32 percent decrease in PDA tumor growth. Other experiments combined the anti-IL-1[beta] antibody, which gloms onto and neutralizes its target, with an already approved antibody treatment that shuts down the protein "checkpoint" called PD1. To spare normal cells from immune attack, the immune system uses checkpoints on immune cells that turn them off when they receive the right signal. Cancer cells hijack checkpoints to turn off the system, leading to immune suppression of CD8+ T cells that would otherwise kill cancer cells. Checkpoint inhibitors counter this effect.


In the current study, adding anti-IL-1[beta] antibodies to anti-PD-1 antibody treatment doubled the infiltration of such T cells into PDA tumors and increased the anti-tumor activity of PD-1 blockade by 40 percent. The new finding is in line with past work in other labs that had described the microbiome, the mix of bacterial species in the pancreas, as being altered in the presence of PDA, and a factor in cancer growth. The field had traditionally assigned the production of IL-1[beta] to immune cells, but the new work finds that pancreatic tumor cells can also make it in response to proteins given off by certain bacteria. Bacterial products were found to activate proteins on the cancer cell surfaces called toll-like receptors, which set off chain reactions that were required for IL-1[beta] production in cancer cells. The research team also found that higher IL-1[beta] production caused nearby pancreatic stellate cells to increase production of dense, structural proteins like collagen. Desmoplasia is the overgrowth of such fibrous tissue that often occurs near pancreatic tumors, and which has been linked to treatment resistance. Active stellate cells were also found to trigger production of the signaling proteins that attract immune cells called macrophages into tumors and programs them to become the type (M2) that suppresses immune reactions. Experiments also confirmed that higher IL-1[beta] and M2 macrophage levels, along with fibroblast-driven desmoplasia, reduced the ability of cancer-cell-killing CD8+ T cells to enter tumors.



Artificial Intelligence for Diagnosis & Grading Of Prostate Cancer in Biopsies: A Population-Based, Diagnostic Study

Researchers have developed a method based on artificial intelligence (AI) for histopathological diagnosis and grading of prostate cancer (Lancet Oncol 2020; doi: 10.1016/S1470-2045(19)30738-7). The AI system has the potential to solve one of the bottlenecks in today's prostate cancer histopathology by providing more accurate diagnosis and better treatment decisions. The study shows that the AI system is as good at identifying and grading prostate cancer as world-leading uro-pathologists. To train and test the AI system, researchers digitized more than 8,000 biopsies taken from some 1,200 Swedish men in the ages of 50-69 to high-resolution images using digital pathology scanners. About 6,600 of the samples were used to train the AI system to spot the difference between biopsies with or without cancer. The remaining samples, and additional sets of samples collected from other labs, were used to test the AI system. Its results were also compared against the assessments of 23 world-leading uro-pathologists.


The findings showed that the AI system was almost near perfect in determining whether a sample contained cancer or not, as well as in estimating the length of the cancer tumor in the biopsy. When it comes to determining the severity of the prostate cancer, the so-called Gleason score, the AI system was on par with the international experts. The initial findings are promising, but more validation is needed before the AI system may be rolled out broadly in clinical practice, according to the researchers. That is why a multicenter study spanning nine European countries is currently underway with completion slated by the end of 2020. That study aims to train the AI system to recognize cancer in biopsies taken from different laboratories, with different types of digital scanners and with very rare growth patterns. In addition, a randomized study starting in 2020 will examine how the AI model may be implemented in Sweden's health care system.



MYC & Twist1 Cooperate to Drive Metastasis By Eliciting Crosstalk Between Cancer & Innate Immunity

Cancer-promoting genes MYC and TWIST1 co-opt immune system cells to enable cancer cells to spread, but blocking a key step in this process can help prevent the disease from developing (eLIFE 2020; doi: 10.7554/eLife.50731). The findings may help clinicians identify cancer patients at risk of metastasis. They may also inform the development of new strategies to prevent or treat metastasis. The researchers genetically engineered mice to express both MYC and TWIST1 and found that these two major cancer-promoting genes led to metastases. They also saw that the cancer cells produced inflammation-promoting molecules CCL2 and IL13, which attract immune cells called macrophages and make them more tumor-cell friendly. This makes it easier for the cancer cells to migrate to new areas of the body. The team next showed that exposing mice with liver cancer (caused by MYC alone) to CCL2 and IL13 causes metastasis. But blocking this specific combination of cytokines appeared to hinder the process.


To see if the two genes also contributed to metastases in humans, the scientists analyzed 10,000 samples of tumors collected from humans with 33 different types of cancer. They found that patients with MYC and TWIST1 were less likely to survive, produced more CCL2 and IL13, and had more macrophages in their tumors. Finally, the team monitored CCL2 and IL13 levels in 25 patients with liver cancer and 10 control patients with cirrhosis. They found that only the patients with liver cancer had elevated levels of the two molecules and, of this group, those with higher levels of IL13 were more likely to have aggressive tumors.



Short-Term Mortality Risks Among Patients With Oropharynx Cancer By Human Papillomavirus Status

New research indicates that there is a higher risk of early death among patients with oropharynx cancer when not caused by human papillomavirus (HPV), than those whose tumors are HPV-positive (Cancer 2020; doi: 10.1002/cncr.32652). The incidence of oropharynx cancer is increasing in the U.S., with rates more than twice as high in men than in women. Recent evidence has shown that approximately 75 percent of these cancers are due to infection with HPV.


The team designed a study to better understand the causes and risks of early death among patients with oropharynx cancer and to determine how these risks differ in patients with and without HPV-related tumors. The researchers' analysis included information on 4,930 U.S. patients who were diagnosed with nonmetastatic oropharynx cancer from 2013 to 2014, including 3,560 whose cancers were HPV-positive and 1,370 whose cancers were HPV-negative. Patients were followed for a median of 11 months. Compared with patients whose cancers were HPV-negative, those whose cancers were HPV-positive had a lower risk of dying from any cause within 2 years (10.4% vs. 33.3%) and a lower risk of dying from head and neck cancer (4.8% vs. 16.2%). Patients who had HPV-positive oropharynx cancer also had a lower risk of dying from cancers other than head and neck cancer.