Introduction
In recent years the role of immune checkpoint molecules has emerged as
one of the most promising avenues of biomolecular and clinical discovery
[1]. The ability to regulate these
molecular regulators represents a new paradigm in directed treatment.
Fundamental to these advances are the ideas of exhausted effector cells,
that is putatively cytotoxic cells that, for one reason or another, have
lost their capacity to effectively participate in anti-tumor responses
[2]. Increases in regulatory T cells,
chronic inflammation, and myeloid and other lineage suppressor cells
have all been implicated in the suppression of immune response and
evasion of tumor cells [3]. More
recently, the so-called checkpoint molecules have risen to the fore.
These include stimulatory molecules (not the subject of this paper), and
inhibitory molecules such as CTLA-4, PD-1, TIGIT, LAG3, Tim-3, VISTA,
Siglec-7, HHLA2, BTLA, and Adenosine A2aR
[4, 5].
Together, or in various combinations, these molecules have been
postulated to form patterns that describe dysfunctional or exhausted T
and NK cells [6,
7]. The roles and distributions of these
molecules may vary between diseases and disease models. In this sense,
similar to other cancers, cervical tumors and advanced dysplasias have
been characterized by various “dysfunctions” of the immune system,
that is failure of immunosurveillance, loss of cytotoxic NK and T
activity, loss of CD3 in TIL and failure to home to tumor sites
[8]. Perhaps some of the most
promising checkpoint markers of immune system dysfunction are PD-1,
TIGIT and Tim-3. While these markers have been established on T cells,
their role in NK cell activity is less well known. To date, PD-1 and
Tim-3 have been found in cervical cancer tissues
[9-11]. TIGIT has yet to be described
in NK cells in cervical cancer or precursor lesions. The role of these
three markers together on the same cells, or on different cell
populations, has only begun to be described in certain models
[12-15]. Recent works have begun to
explore the role of different sub-populations within effector cells,
that is populations that express sharply higher levels of PD-1 as a way
of distinguishing the expected presence of “normal” checkpoint
molecules (which may be physiologically expected in healthy populations)
and pathogenic levels, that may be encountered in select patients
[16]. The accurate distinction
between these two groups may define the difference between tumors
responsive to, or refractory to, current and future immunotherapy
checkpoint blockades. The goal of this current paper is to characterize
different NK and T cell populations with respect to checkpoint molecules
in cervical cancer patients.