Targeting Immune Cells That Aid Tumor Growth May Enhance Tumor Response To Immunotherapy

Highlights:

• Immunotherapy, a form of treatment for cancers aims to enhance the tumor fighting ability of the immune system and destroy tumor cells
• Current study suggests that certain immune cells (neutrophils) may actually help tumor growth and survival and dampen response to immunotherapy in lung tumors
• Targeting neutrophils may enhance tumor response to immunotherapy.

Scientists in Switzerland have discovered that certain immune cells (neutrophils) that normally help to fight infection may actually aid in tumor progression and dampen response to immunotherapy in lung tumors.

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Trying to Beat Lung Tumors at their Own Game

Lung cancer is the most important cause of cancer associated deaths. More recently, promising ways to treat lung cancers include immunotherapy which aims to enhance the immune system’s ability to fight the tumor as well as block the tumor cell’s attempts at evading the immune system. However, lung cancer treatment poses a challenge – the tumors find ways and means to evade the host immune system, making response to immunotherapy less than optimal.

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Immunotherapy Blocking PDL1-PD1 Interaction Not Enough – Looking for New Targets

One of the ways that lung tumors evade the immune system is by expressing a protein termed programmed death ligand 1 (PDL1) on their surface. When T cells of the immune system attack the tumor, the PDL1 protein binds to the corresponding protein on the surface of the T cells called programmed cell death protein-1 or PD-1. This interaction closes down the tumor fighting machinery of the T cells and renders them ineffective to the lung tumor cells.

Naturally, many immunotherapy regimens consist of agents that block the PDL-1 and PD-1 interaction but this does not appear to have been sufficient to obtain the desired response.

The current study, conducted at the Ecole Polytechnique Federale De Lausanne (EPFL), hopes to further probe into the various immune circuits that may be active in lung tumors, understand the mechanisms at play and identify newer targets to optimize and improve the effectiveness of immunotherapy in lung cancer.

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Neutrophils, the Enemy Within – Aiding Tumor Progression

Using a mouse lung cancer model to study the immune mechanisms at play in lung cancer, the research team of Etienne Meylan at EPFL found to their surprise the following

• Neutrophils, a type of white blood cell important as first line defence in infections, allergies and asthma might be helping tumor growth and progression instead of preventing it
• On depleting neutrophils (neutrophil depletion), they saw the tumor being flooded with T cells which suggested that the neutrophils were actually helping the tumor hide from the T cells, a phenomenon referred to as immune exclusion.
• However, on the flip side, neutrophil depletion sensitized the lung tumor to PD-1 blocking agents.

"Since neutrophils are important in fighting pathogens, neutrophil depletion is unlikely to be used in the clinic," says Meylan. "Instead, we must concentrate our efforts to understand exactly how neutrophils promote lung tumor development. This could lead to the identification of drugs that block this specific pro-tumor function of neutrophils."

• Neutrophils also helped the tumor progress and grow by causing changes in the tumor blood vessels that caused low oxygen tension (hypoxia) within the tumor
• In response to hypoxia, the tumor cells secreted a protein called Snail, which has been found to promote tumor metastasis, cause recurrence and resistance to anti-cancer agents
• Also, the Snail protein caused secretion of Cxcl2, a protein that caused increased infiltration of neutrophils in the tumor microenvironment.

Thus, a positive loop is created that promotes tumor progression and resistance to treatment; this ‘vicious cycle’ could seriously hamper the effectiveness of immunotherapy by maintaining a tumor milieu conducive to tumor growth and progression.

"Immunotherapies constitute new treatment options with important clinical success for this devastating disease," says Etienne Meylan. "But in up to two thirds of patients the lung tumors do not respond. We believe our work offers one explanation for this; finding new ways to break the vicious dialogue between neutrophils and tumor cells might impair tumor growth, and also increase the percentage of patients that benefit from immunotherapy."

Current status of Immunotherapy in Lung Cancer

Immunotherapy or biologic therapy is a form of cancer therapy that boosts the body’s natural defenses to fight the tumor cells.

Currently, the U.S. Food and Drug Administration (FDA) has approved the checkpoint inhibitor agents pembrolizumab (Keytruda^®), nivolumab (Opdivo^®) and atezolizumab (Tecentriq^®) in the treatment of non-small-cell lung cancer. These drugs block PD-1 and PD-L1 interaction, (which is one of the mechanisms that tumor cells use to evade the immune system) and improve the immune system’s ability to attack the tumor.

Immunotherapy may not be ideal for all patients, and responses differ widely. It may also be used in combination with surgery or chemotherapy as well. Pembrolizumab has been approved by the FDA in combination with chemotherapy as a first line therapy in some cases of non-small cell lung cancer.

References:

1. Julien Faget, Svenja Groeneveld, Gael Boivin, Martial Sankar, Nadine Zangger, Miguel Garcia, Nicolas Guex, Inti Zlobec, Loïc Steiner, Alessandra Piersigilli, Ioannis Xenarios, and Etienne Meylan. Neutrophils and Snail Orchestrate the Establishment of a Pro-tumor Microenvironment in Lung Cancer. Cell Reports. Volume 21, Issue 11, p3190–3204, 12 December 2017
2. Immunotherapy for lung cancer - (https://www.cancercenter.com/lung-cancer/immunotherapy/)

Source-Medindia