Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients

Niels Halama, Inka Zoernig, Anna Berthel, Christoph Kahlert, Fee Klupp, Meggy Suarez-Carmona,Thomas Suetterlin, Karsten Brand, Juergen Krauss, Felix Lasitschka, Tina Lerchl, Claudia Luckner-Minden, Alexis Ulrich, Moritz Koch, Juergen Weitz, Martin Schneider, Markus W. Buechler, Laurence Zitvogel,
Thomas Herrmann, Axel Benner, Christina Kunz, Stephan Luecke, Christoph Springfeld, Niels Grabe, Christine S. Falk, and Dirk Jaeger

Targeting Tumor-Promoting Microenvironment Through CCR5 Blockade in Metastases

progression is a process in which cancer cells and cells interact with each other in a way that can lead to the growth and spread of cancer. In cancer, when the cancer has spread to other parts of the body, it is called and it is very difficult to treat. Treatments such as PD-1/PD-L1 blockade and modulation have been successful in modifying the interactions between the immune system and cancer, leading to the rejection or suppression of progression. Cancer cells can also alter the immune microenvironment, leading to and evasion. In this research paper, the authors studied the microenvironment in metastases and identified a network of cells and immune cells that exploit the CCL5-CCR5 axis. They then investigated and characterized the effects of blocking the CCL5-CCR5 axis.

the microenvironment of metastases of cancer ().

the environment induces migration of T lymphocytes, which produce a called CCL5. This CCL5 then supports tumor growth and spread by influencing macrophages and cells. The environment is immunosuppressive and the tumor cells are exploiting the host's cells to their advantage. In other words, the tumor cells are using the host's immune cells to help them grow and spread.

the effects of CCR5 blockade on the level.

Tumor death and a specific pattern of and modulation are observed in the and in biopsies from a . Macrophages are the key for these anti-tumoral effects, as they produce IFNs and reactive oxygen species which cause tumor cell death. blockade induces a phenotypic shift in the macrophages, which is referred to as a switch from an M2 to an M1 phenotype. This repolarization also reduces levels of CD163+ cells, reshaping the cell composition in the microenvironment. The influx of new effector cells due to CCR5 inhibition can shift the effects of CCL5 towards beneficial effects, such as reduction of , , and resistance.

The microenvironment of the invasive margin of metastases.

There was no relevant Th1, Th2, or Th17 signature present in any of the samples. However, the authors did find that and -related cytokines were significantly increased at the invasive margin. Chemokines are molecules that help to attract cells to the area, and macrophage-related cytokines are molecules that help to regulate the activity of , which are a type of immune cell. 98% of the CD3+ s in the resection specimens were positive for PD-1, which is a molecule that helps to regulate the activity of the immune system.

is a protein produced by T cells, which are a type of white blood cell. is a receptor found on metastatic tumor cells, which are cancer cells that have spread from the primary to other parts of the body. In this research paper, it was found that CCL5 has tumor-promoting effects on cells and tumor-associated s. This means that CCL5 has multiple effects on both the cancer cells and the macrophages, which are a type of white , that are associated with the . CCL5 was produced mainly by T cells located at the invasive margin and stroma of metastases, and that CCR5 was dominantly expressed by metastatic tumor cells. CCL5 also had effects on tumor , invasive tumor , and increased production of matrix es by tumor-associated macrophages. Finally, they found that CCR5 inhibition had an effect on key molecules of to transition ( ).

The researchers wanted to test the effects of blockade, which is a way of blocking the CCR5 receptor on cells, using a drug called maraviroc. They used human s, which are samples of from advanced patients with metastases. Maraviroc led to morphologically overt tumor in the , which means that the tumor cells died and changed in appearance. The researchers then tested the hypothesis that s, (type of white blood cell), were required for the tumor cell death-inducing effects of CCR5 blockade. They used clodronate s to deplete CD163+ TAMs, ( s associated with tumors) and found that combining clodronate with CCR5 inhibition abrogated the immediate tumor cell death-inducing effects of inhibition. This confirmed the role of macrophages in this process. IFN-g induced stromal CD163+ death and led to a reconfiguration of the cell compartment. Inhibition of macrophage-derived reactive oxygen species could partially block the anti-tumoral effects of CCR5 inhibition. Finally, they tested the effects of CCL5/CCR5 inhibition and found that both a CCL5 neutralizing antibody and a CCR5 blocking had similar functional effects to maraviroc.

A (MARACON) was conducted to test the effects of a drug called maraviroc on patients with advanced-stage colorectal . The involved taking biopsies of the patients before and after treatment with maraviroc, and the results showed that the drug had beneficial effects on the tumor-promoting and led to objective clinical responses. These responses included induction of central , reduction of tumor cell death, and reduction of key s and growth factors that promote tumor growth. The drug was also found to be very well tolerated, with mild elevation of enzymes being the most common side effect. Finally, the trial showed that partial responses were achieved in patients with previously refractory disease.

CCR5 blockade, is a type of used to treat .

The MARACON clinical trial, showed that CCR5 blockade had a positive effect on the tumor microenvironment and led to a higher response rate in subsequent chemotherapies. The authors suggest that this effect is not limited to the metastases, but is a systemic feature. They also suggest that the local presence of multiple layers of subversion in cancers depends on the individual tissue, , tumor type, and the difference between primary and metastatic lesion. The authors also found that the results of the were in line with the results of a fully human organotypic tumor , which is a simple model with a straightforward approach. The authors also note that the survival data from the trial is not conclusive due to the limited number of patients, but that the objective treatment responses are very encouraging. They suggest that CCR5 blockade may be a promising approach and needs to be evaluated further scientifically and clinically.

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