Introduction
The progression of lung cancer is known to be linked with an overall
weakened antitumor immunity[1] . Therefore, novel approaches
for its treatment have been developed with the key objective of
inhibiting this attenuated immune mechanism on one hand and activating
self-defense [2] . Tremendous progress has been made to
unveil the mechanism of the immune cell defense against cancer cells,
presenting new and promising therapies based on new immunotherapy,
represented in Immune checkpoint inhibitors, Antigen-specific vaccines
and Adoptive T cell transfer (CAR T-cell), which augment the immune
system in targeting cancer cells [3] . These promising
methods can potentially provide long term cancer remission without
causing the same side effects evident when using chemotherapeutic agents
and radiation. In addition, they hold great promise in improving the
prognostic outcomes of lung cancer patients, overcoming the hurdle of
the poor overall 5-year survival rate barely ranging between 5-15%
[4].
Lung cancer cells elicit an immune response that recruits cytolytic
immune cells including cytotoxic T cells (CD8+) and
natural killer cells (NK). These cells are able to remove harmful cells
via the release of the cytolytic content of their granules such as
perforin(Pr), granzymes (Gzs) and interferon-gamma (IFN-γ) into the
cytosol of targeted cells ultimately leading to decomposing these cells[5] . Granzymes have the ability to target cells promoting
downstream caspase activation and cell death. However, out of this
serine protease granzyme family, Granzyme B (GzB) poses the major
constituent excreted by CD8+ and NK and holds the
strongest apoptotic activity of all Gzs [6] . Therefore, the
ability of cancer cells to resist these cytolytic mediators plays a
vital role in their continued existence and expansion.
Addressing the functionality of immune cells is of major importance to
enable the evolvement of more effective immunotherapeutic approaches.
Previous studies have demonstrated that lung cancer is associated with a
locally decreased expression of GzB, Pr and IFN-γ by the
tumor-infiltrating CD8+ T cells, NK and NK T like
cells in the tumor microenvironment by the effect of lung cancer
mediators like prostaglandin E2 (PGE2), transforming growth factor
(TGF)-β) which have a relationship with assisting tumor cell
proliferation, anti-apoptotic properties, angiogenesis and
chemotherapeutic resistance [7, 8] . These alterations
within the tumor microenvironment were found to impair the functionality
of these cells and reduce the effectiveness of the adaptive immune
responses against cancer cells. Accordingly, the hypothesis that this
dysfunction extends beyond the confined boundaries of the tumor
microenvironment has been validated [9] . we conducted the
previous study concluded that the numbers of CTLs and NK cells and their
expression of GzB were reduced in newly diagnosed lung cancer patients[10] .
In This study, we aim to address the number and functionality of CD4,
CD8, NK, NKCD4 and NKCD8T cell in lung cancer patients before, during
and after induction of chemotherapy and their intracellular expressions
of GzB versus the inflammatory and prognosis cytokines and interleukins
correlates it with the clinical response of patients in order to
activation conditions with Concanavalin A (Con A) and Interleukin-2
(IL-2) in certain settings of culture in-vitro .