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.