News | Radiation Therapy | July 22, 2020

Study Finds Reprogramming of Immune Cells Enhances Effects of Radiotherapy in Preclinical Models of Brain Cancer

 A Ludwig Cancer Research study has dissected how radiotherapy alters the behavior of immune cells known as macrophages found in glioblastoma (GBM) tumors and shown how these cells might be reprogrammed with an existing drug to suppress the invariable recurrence of the aggressive brain cancer.

July 22, 2020 — A Ludwig Cancer Research study has dissected how radiotherapy alters the behavior of immune cells known as macrophages found in glioblastoma (GBM) tumors and shown how these cells might be reprogrammed with an existing drug to suppress the invariable recurrence of the aggressive brain cancer.

Led by Ludwig Lausanne Member Johanna Joyce and published in the current issue of Science Translational Medicine, the study details how radiotherapy dynamically alters gene expression programs in two subtypes of tumor-associated macrophages (TAMs) and describes how those changes push TAMs into a state in which they aid therapeutic resistance and growth. Joyce and her colleagues, led by first author Leila Akkari, now at the Netherlands Cancer Institute, also demonstrate that combining radiotherapy with daily dosing of a drug that targets macrophages—an inhibitor of the colony stimulating factor-1 receptor (CSF-1R) — reverses that transformation and dramatically extends survival in mouse models of GBM. 

“What these preclinical data tell us is that for patients receiving radiotherapy for glioblastoma, adding CSF-1R inhibition to the treatment regimen could have the effect of prolonging survival,” said Joyce.

GBM patients typically survive little more than a year following diagnosis, as the cancer inevitably recurs and typically resists multiple therapies. But it was not known whether TAMs—which are linked to cancer cell survival and drug resistance in a variety of tumor types — promote GBM resistance to ionizing radiation, which is part of the standard of care for the aggressive tumor.

Two types of macrophages populate glioma tumors. One is the brain’s resident macrophage, or microglia (MG). The other is the monocyte-derived macrophage (MDM) that patrols the body, gobbling up pathogens and dead cells, or their detritus, and initiating additional immune responses. Macrophages can, however, be pushed into an alternative state — often termed the M2-like activation phenotype — in which they aid tissue healing rather than respond to threats. Many cancers coax macrophages into this alternative phenotype, which supports tumor survival and growth.

Joyce and her team found both MG and MDMs flood into GBM tumors in mice to clean up the cellular detritus following an initial course of radiotherapy. But when the gliomas recur, interestingly, it is MDMs that predominate in the TAM populations. The gene expression profiles of these MDMs in irradiated tumors, however, more closely resembles those of MG. They found, moreover, that both MDMs and MG in irradiated gliomas are alternatively activated into a wound-healing phenotype and secrete factors that bolster DNA repair in cells.

“Not only were these macrophage populations changing but, more importantly, they were now able to interfere with the efficacy of radiotherapy because they could help cancer cells repair the DNA damage it causes,” explained Joyce.

“So you have this yin/yang situation. The irradiation is of course destroying many of the cancer cells, but it has also caused all these macrophages to rush into the tumor to clean up the mess and, as a consequence, they’ve been super-activated to create a permissive niche for the remaining cancer cells to form new tumors.”

To see if depleting MDMs specifically might reverse that effect, the researchers treated different GBM mouse models with an antibody that blocks the entry of MDMs into the brain. But that only nominally improved survival in one of the models.

The Joyce lab has previously reported that TAMs can be pushed out of the wound-healing phenotype by CSF-1R inhibitors, so they next tested whether that strategy might bolster the efficacy of radiotherapy.

They found that a single, 12-day cycle of CSF-1R inhibitor treatment following radiotherapy enhanced the initial therapeutic response and extended the median survival of mice by about three weeks beyond the modest increase seen with radiotherapy alone. By contrast, a continuous, daily regimen of CSF-1R inhibition for several months following radiotherapy yielded the most striking results, reprogramming TAMs and dramatically extending median survival.

“We had approximately 95% of mice survive the full course of this six-month study,” said Joyce. In addition, mice engrafted with patient-derived tumors showed increased survival.

Joyce and colleagues are further exploring the mechanism by which TAMs promote DNA repair and otherwise assist cancer cell survival in GBM.

For more information: www.ludwigcancerresearch.org

Related Content:

SNMMI Channel

PSMA PET/CT Can Change Management in Recurrent Prostate Cancer

Total-body Dynamic PET Successfully Detects Metastatic Cancer

New PET Radiotracer Proven Safe in Imaging Malignant Brain Tumors

Targeted Radionuclide Therapy Enhances Prostate Cancer Response to Immunotherapies

New PET/MRI Approach Pinpoints Chronic Pain Location, Alters Management

Related Content

"Our study demonstrates that a real-world lung cancer screening can perform similar to randomized controlled trials in regard to important performance metrics," the UPenn authors of this AJR article concluded. Image courtesy of American Journal of Roentgenology (AJR)

"Our study demonstrates that a real-world lung cancer screening can perform similar to randomized controlled trials in regard to important performance metrics," the UPenn authors of this AJR article concluded. Image courtesy of American Journal of Roentgenology (AJR)

News | Lung Imaging | July 17, 2020
July 17, 2020 — An online first accepted...
PSMA PET/CT accurately detects recurrent prostate cancer in 67-year-old man. 18F-DCFPyL-PSMA PET/CT shows extensive, intensely PSMA-avid local recurrence in prostate (bottom row; solid arrow) in keeping with the known tumor recurrence in the prostate. Right: PET shows extensive, intensely PSMA-avid local recurrence in prostate (top row; solid arrow) and a solitary bone metastasis in left rib 2 (bottom row; dotted arrow). Image courtesy of Ur Metser, et al.

PSMA PET/CT accurately detects recurrent prostate cancer in 67-year-old man. 18F-DCFPyL-PSMA PET/CT shows extensive, intensely PSMA-avid local recurrence in prostate (bottom row; solid arrow) in keeping with the known tumor recurrence in the prostate. Right: PET shows extensive, intensely PSMA-avid local recurrence in prostate (top row; solid arrow) and a solitary bone metastasis in left rib 2 (bottom row; dotted arrow). Image courtesy of Ur Metser, et al.

News | PET-CT | July 16, 2020
July 16, 2020 — New research confirms the high impact of...
Total-body dynamic 18F-FDG PET imaging with the uEXPLORER scanner allows us to monitor the spatiotemporal distribution of glucose concentration in metastatic tumors in the entire body (a). As compared to a typical clinical standardized uptake value image (b), the parametric image of FDG influx rate (Ki) can achieve higher lesion-to-background (e.g., the liver) contrast. In addition to glucose metabolism imaging by Ki, total-body dynamic PET also enables multiparametric characterization of tumors and organs

Total-body dynamic 18F-FDG PET imaging with the uEXPLORER scanner allows us to monitor the spatiotemporal distribution of glucose concentration in metastatic tumors in the entire body (a). As compared to a typical clinical standardized uptake value image (b), the parametric image of FDG influx rate (Ki) can achieve higher lesion-to-background (e.g., the liver) contrast. In addition to glucose metabolism imaging by Ki, total-body dynamic PET also enables multiparametric characterization of tumors and organs using additional physiologically important parameters, for example, glucose transport rate K1 (d), across the entire body. Image courtesy of G.B. Wang, M. Parikh, L. Nardo, et al., University of California Davis, Calif.

News | PET Imaging | July 16, 2020
July 16, 2020 — Results from the first...
World's largest radiation oncology meeting will offer full conference on interactive platform October 25-28, 2020
News | ASTRO | July 09, 2020
July 9, 2020 — Registration opens today for the American Society for Radiation Oncology's (...
Simulation finds starting at age 30 with MRI and mammography to be the preferred strategy; starting at 25 prevented marginally more deaths, but with more testing and emotional stress

Getty Images

News | Breast Imaging | July 09, 2020
July 9, 2020 — Chest radiation is used to treat children with Hodgkin and non-Hodgkin lymphoma as well as lung metast
At the American Association of Physicists in Medicine (AAPM) 2019 meeting, new artificial intelligence (AI) software to assist with radiotherapy treatment planning systems was highlighted. The goal of the AI-based systems is to save staff time, while still allowing clinicians to do the final patient review. 
Feature | Treatment Planning | July 08, 2020 | By Melinda Taschetta-Millane
At the American Association of Physicists in Medicine (AAPM) 201
Changes outlined in new draft U.S. Preventive Services Task Force (USPSTF) lung cancer screening recommendations will greatly increase the number of Americans eligible for screening and help medical providers save thousands more lives each year.

Image courtesy of Cerner

News | Lung Imaging | July 08, 2020
July 8, 2020 — Changes outlined in new draft U.S.
Radiotherapy has been used to treat cancers for more than a century and continues to be utilized in cancer treatment plans today. Since the introduction of radiotherapy, clinicians have been working tirelessly to further refine treatments to better target cancer.
Feature | Radiation Therapy | July 06, 2020 | By Yves Archambault
Everything has room for improvement, right? Right. When it comes to cancer care, it is no different.
Proton therapy has evolved, and future predictions include smaller systems, more sophisticated proton dosimetry and devices that manipulate the proton beam
Feature | Proton Therapy | July 06, 2020 | By Minesh Mehta, M.D.
The field of proton...