This study represents the inaugural comprehensive investigation employing Mendelian Randomization (MR) to elucidate the causal dynamics between an extensive array of 731 immune phenotypes and endometrial cancer, inclusive of its various subtypes. Through this analysis, we identified a causal association of three specific immune phenotypes with the non-endometrioid subtype of endometrial cancer. These phenotypes are characterized by CD28 + CD45RA + CD8dim T cells and CD64 expression on CD14 + CD16 + monocytes. Notably, an upsurge in the absolute values or proportions of CD28 + CD45RA + CD8dim T cells correlates with increased risk for non-endometrioid endometrial cancer. In contrast, CD64 expressed on CD14 + CD16 + monocytes emerges as a protective factor against this cancer subtype.
The prevailing clinical research landscape offers limited insights into the role of these immune phenotypes in endometrial cancer. Our findings contribute pivotal evidence suggesting that immune cells, through a genetic framework informed by large-scale GWAS summary data, can modulate the risk associated with non-endometrioid endometrial cancer. This hypothesis is further corroborated by parallel findings in other studies, such as the observed elevation in CD8 + CD28-T cell counts in Cervical Intraepithelial Neoplasia (CIN) patients[20].
CD45RA, a cell surface molecule predominantly expressed on 'naive' T cells, signifies a population of T cells yet to encounter their specific antigen, and thus, remain in an unactivated state[21]. Cells expressing CD45RA typically exhibit extended longevity and heightened proliferative capacity. Additionally, CD64 presence on CD14 + CD16 + monocytes is indicative of a more activated and mature monocyte phenotype, marked by robust phagocytic functionality and an augmented inflammatory response[22]. This attribute is crucial in various inflammatory scenarios, infections, and certain autoimmune disorders, where these cells play an essential role in pathogen recognition, phagocytosis, inflammatory cytokine production, thus constituting a vital component of immune defense and pathophysiological mechanisms[23].
The human immune system is intricately structured into two principal and synergistic subsystems: (1) The innate immune system, encompassing dendritic cells, natural killer (NK) cells, monocytes, neutrophils, eosinophils, basophils, and mast cells. This subsystem operates autonomously, not contingent on previous antigen exposure. (2) The adaptive immune system, composed of B lymphocytes, cluster of differentiation 4 (CD4+) helper T lymphocytes, and cluster of differentiation 8 (CD8+) cytotoxic T lymphocytes, necessitates antigenic priming facilitated by antigen-presenting cells (APCs) for effective activation[24]. A pivotal function of immune cells is the identification and eradication of cancer cells through the recognition of tumor-specific antigens (TSAs) and tumor-associated antigens (TAAs)[25].
Our research delineates the involvement of two specific T cell subtypes in the progression of non-endometrioid endometrial cancer. The CD45RA + CD28-CD8 + T cells, typically classified as 'experienced' due to their surface expression of the naive T cell marker CD45RA, may represent terminally differentiated or 'exhausted' T cells, especially considering their lack of CD28[26]. This phenotype potentially translates to diminished cellular activity and proliferative capabilities. In contrast, CD28 + CD45RA + CD8dim T cells display more 'naive' traits, with an inherent activation potential facilitated by the presence of CD28. The 'CD8dim' designation implies a possible attenuation in their cytotoxic potential[27]. The exact operational mechanisms of these cells in the context of endometrial cancer warrant comprehensive exploration and verification through advanced clinical studies.
The burgeoning field of immunotherapy in the management of endometrial cancer represents a dynamic and evolving area of research. Central to these therapeutic strategies is the activation or augmentation of the patient's intrinsic immune response to combat malignancy. Specifically in endometrial cancer, the efficacy of programmed death-1/ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors has been substantiated, serving to stimulate T cell activation and thereby enhance their cancer cell targeting capabilities[28, 29].
Notably, endometrial tumors characterized by high microsatellite instability (MSI-H) demonstrate a propensity for a more favorable response to immunotherapeutic interventions. These MSI-H tumors are distinguished by an elevated mutational burden, which may lead to the generation of an increased array of neoantigens, thus eliciting a more potent immune reaction. Parallel to MSI, a high tumor mutational burden (TMB) is increasingly recognized as a predictive marker for a positive immunotherapy response, with high TMB tumors potentially exhibiting enhanced visibility and susceptibility to immune system attack[30].
Emergent forms of immunotherapy, including cell-based therapies, involve the extraction, ex vivo modification or amplification of patient-derived immune cells (e.g., T cells), followed by their reinfusion to facilitate targeted cancer cell eradication. Additionally, cancer vaccines represent a novel therapeutic avenue. Though still in the experimental phase for endometrial cancer, these approaches manifest promising potential for future clinical application. Complementing these advancements, our research underscores the significance of specific immune cell subtypes in the pathogenesis of non-endometrioid endometrial cancer, further informing the potential for targeted immunotherapeutic strategies.
Intriguingly, this Mendelian Randomization (MR) analysis negated any causal links between endometrioid endometrial cancer and all subtypes of endometrial cancer in relation to genetically predicted immune phenotypes. To corroborate this finding, we rigorously evaluated four additional Genome-Wide Association Study (GWAS) datasets through meta-analytical methods, consistently reaffirming this conclusion. This outcome prompts a compelling inquiry into the unique characteristics of type 2 endometrial cancer and its immune profile, underscoring the need for more in-depth investigation.
Presently, immunotherapeutic research predominantly demonstrates notable efficacy in patients exhibiting Microsatellite Instability-High (MSI-H) and deficient Mismatch Repair (dMMR) phenotypes. Given these insights, future research trajectories should pivot towards exploring type 2 endometrial cancer. The objective would be to develop and refine more targeted, individualized therapeutic interventions, catering to this subtype characterized by its heightened aggressiveness and comparatively adverse prognosis.
This investigation employs a two-sample Mendelian Randomization (MR) approach, leveraging data from extensive Genome-Wide Association Study (GWAS) cohorts. The considerable sample size of these cohorts enhances the statistical robustness and efficiency of our analysis. Our study's conclusions are grounded in the application of genetic instrumental variables, alongside the employment of various MR methodologies for robust causal inference. The outcomes of our analysis demonstrate resilience, remaining unswayed by horizontal pleiotropy or other potential confounders.
Nevertheless, it is crucial to acknowledge the intrinsic limitations characteristic of MR studies. It is important to note that MR analysis, while valuable for elucidating causal relationships between exposure and outcome, is not a substitute for empirical clinical trials. As such, additional research is imperative to substantiate the suspected link between immune cells and non-endometrioid endometrial cancer.
A limitation of our study is its exclusive focus on European populations, dictated by the current availability of GWAS datasets. This restriction is significant considering the genetic diversity across various ethnic groups, which may lead to differential results in diverse populations. Future research, therefore, should aim to incorporate subgroup analyses across a range of populations to ensure the derivation of more universally applicable conclusions.