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.
- 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.
Trying to Beat Lung Tumors at their Own Game
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
tumors find ways and means to evade the
host immune system
, making response to immunotherapy less than optimal.
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 programed 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 programed 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.
‘Future research should focus on new therapies to break the neutrophil – tumor loop that promotes lung tumor growth and lowers response to immunotherapy’
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.
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
- 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."
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
- 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.
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
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
Currently, the U.S. Food and Drug
Administration (FDA) has approved the checkpoint
inhibitor agents pembrolizumab (Keytruda®), nivolumab (Opdivo®) and atezolizumab (Tecentriq®)
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.
- 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
- Immunotherapy for lung cancer - (https://www.cancercenter.com/lung-cancer/immunotherapy/)