T cell subset—an overview in oral submucous fibrosis and oral squamous cell carcinoma in background of oral submucous fibrosis

Introduction

Over one billion people use tobacco products globally, and over 12% of deaths in people aged more than 30 years are attributed to tobacco use (1). Many studies have been done to analyze the effects of chewing tobacco on human body homeostasis; these studies include analyzing cancerous effects, toxicities, role in the induction of inflammatory microenvironments in various organs, and some basic analysis regarding the basic immune functions. Indian population has case-control reports which identify tobacco chewing as a menacing factor for many oral potentially malignant disorders (OPMDs) and oral cancer related to smoking and non-smoking tobacco (1,2).

Oral squamous cell carcinoma (OSCC) accounts for approximately 90% of all oral malignancies, being the sixth most common globally (1). In a few South Asian countries including India, OSCC is still more predominant compared with others (2). This erraticism in the universal frequency of OSCC has been accredited to social habits, including the intake of tobacco, alcohol, and areca nut. These tumors are habitually confined, and exophytic, and are frequently related to vital immunosuppression chiefly in the progressive stage. Recent studies concerning the immune system have discovered that host immunity can affect tumor growth, accenting the position of immunological biomarkers regarding treatment and its prognostic approach in cancer cases (3,4). In about one-third of the cases, OSCC might occur by OPMD (5).

Oral submucous fibrosis (OSF) is a precancerous condition with marked alteration in fibers of connective tissue concerned with the lamina propria and its deeper position. In the period of about 10 years the OSF has shown 7.6% of the malignant transformation (MT) rate (6). In Indian countries, OSF signifies a public health problem, with studies have been associated with use of areca nut, a known potentially carcinogenic entity. However, the mechanisms behind it have not been proven (2,7). The OSF linked with OSCC (OSF-OSCC) is known to be usual malignant neoplasm in areas of South and Southeast Asia (6). It appears that the OSCC developing from OSF and that arising from oral leukoplakia convey generally variable prognostic inferences. The immune system is also known to play the utmost significant part in the regulation of OPMD and frank invasive lesions.

The immune cell infiltrates seen in early OSF consist of neutrophils and eosinophils and in the later stage, lymphocytes and plasma cells are more which are of chronic types. It has also been studied that mast, macrophages, Langerhans’ cells other than T cells also has part in the pertinence with immunomodulation in occurrence and development of OSF (8).

With the progress of time, it is getting very apparent that numerous subsets of T cells have a key part in the maintenance of body homeostasis. Several researchers are concerned about the T cell subset counts and functionality in various diseases, where research groups are trying to establish links between T cells profiles and pathological symptoms or the predisposition for the disorders. The passable host immune response defends the mucosa from its malignant change (9). The knowledge regarding analyzed data of T cell subsets including T helper cell subgroups [Th1, Th2, Th17, and regulatory T cells (Tregs)], both for their percentages and functionalities and secondly, the profile analysis of studies based on the memory and readiness to combat infectious and cellular diseases (all subsets of memory cells) is required to understand the pathogenesis. Tobacco chewing harms the homeostasis of the body, generates an inflammatory situation, weakens the immune response, and makes the body prone to the onset of cancer is a well-known fact (10). Taking this as background, this review gives the essential role of T cells and their subsets to understand detailed T cell profiling in OSF cases and OSCC in background of OSF. The databases like PubMed and Science Direct were searched under leading related keywords: “T cell subsets”, AND “oral submucous fibrosis” AND/OR “oral squamous cell carcinoma”, AND/OR “oral squamous cell carcinoma in background of oral submucous fibrosis”, AND/OR “immune system”.

Immune system and OSCC

The immune and inflammatory responses to OSCC are multifaceted and have significance in the advancement and disease prognosis. In the protection against cancer, the immune system has a major role, which was already made known at the start of 1970s itself by Noone and his co-researchers about the prognostic state of OSCC which got better if T lymphocytes were seen in tumor (11). The cancer immunosurveillance hypothesis states recognizing the cancer precursor cells by the immune system and destruction by them (12). Nevertheless, the recently presented idea of cancer immunoediting is directed as an impulsive interface in between the immune system and tumor or dysplastic cells, along with proper stages of eliminating, balancing, and escaping (11-13). An amplified amount of Tregs was noted with peripheral blood, lymph nodes, and tumor cells in cases of OSCC (14,15). The prognostic value was seen with the existence of tumor-infiltrating lymphocytes (TILs) which could reflect the response of the host immune towards tumor cells (16). Tregs are also required in maintaining the oral mucosa concerning immune tolerance. Though noted increased amount of Tregs in oral cancer, the consequence of this spectacle is controversial and their increase is connected to improvement in the OSCC prognosis. A better patient survival rate was noted in one study, which showed high in “CD4⁺, CD25, and CD127” cells in early-stage OSCC associated with late-stage (17). The high levels of tumor-infiltrating Tregs were connected to the low rate of metastasis in lymph nodes, and higher entity of forkhead box P3 (FOXP3)⁺ T cells were considerably connected with allover extended survival rate (18). Aggarwal et al. also showed more Treg subsets with the progression of the tumor, with advanced cases and in large tumors and node involvement. Thus, all the above-mentioned studies give the inference of the increased occurrence of Treg cells must be contributory to the increased ratio of “CD3⁺ and CD4⁺ T cells” (19).

T cells and OSF

The immune system is also noted to regulate OPMD and even the lesions of frank invasive. The study done by Sirsat et al. on OSF tissue by different stains like hematoxylin-eosin, Mallory’s trichome, etc. showed the presence of inflammatory cells within all the OSF stages. They found in the first stage predominantly polymorphonuclear leukocytes and occasionally eosinophils, in second stage mononuclear lymphocytes, eosinophils, and episodic plasma cells, and existence of lymphocytes and plasma cells pertaining to advanced and moderately advanced cases of OSF were showed (20).

Haque et al. [1997] established the infiltration of inflammatory cells in the OSF tissue which comprised mainly of T lymphocytes. They showed the activated CD3⁺ T lymphocytes, CD4⁺ helper/inducer T lymphocytes, and some dispersed CD8⁺ suppressor/cytotoxic T lymphocytes. The casual infiltration of CD20⁺ B lymphocytes and CD68⁺ cells which belongs to macrophages and Langerhans’ cells were found in tissues of OSF (21).

Haque et al. [1998] in their further research study on OSF inspected the existence and allocation of cells pertaining to inflammation and major histocompatibility complex (MHC) class II antigen representation with epithelium and cells of immunocompetent by immunoperoxidase method on frozen tissues (22). Antibodies to all T cell subsets (CD3, CD4, CD8, CD20), naive T cells and monocytes (CD45RA), macrophages, Langerhans’ cells (CD68), positive human leukocyte antigen-DR cells (HLA-DR alpha) were investigated (23). Predominantly the CD3, CD4, and HLA-DR-positive cells found detected in OSF comparing with the control. Some of dispersed CD8-positive cells and just infrequent cells of CD20 and CD68-positive were reported in OSF. The existence of above-mentioned immunocompetent cells with higher proportion of CD4 to CD8 propose a continuing cellular immune event directing towards likely disparity of immunoregulation and architectural modification of the tissue (21,22).

Yet, the above referred studies are inferences based on qualitative investigation of inflammatory component in tissues of OSF, and quantitative analysis of it is still not reported for OSF tissues. Increased infiltration of activated lymphocytes in the epithelium and sub-epithelium specifies greater local inflammatory reaction and recommends amplified production of immunomodulatory cytokine. It is not even distinct that the type of CD4 cells (Th0, Th1-like, and Th2-like) are predominantly needed in OSF for releasing cytokines. Certain set of lymphocytes might give cytokines pertaining to antifibrosis, including IFN-7, due to the deficiency of HLA-DR countenance on cells of epithelium proposes that these particular cells might not be chiefly intricated in the pathology (21).

Analyzing quantitatively for the immunocompetent cells comparing moderately advanced and advanced OSF tissue discovered that the density of T lymphocytes and macrophages of the epithelium and in subepithelium was significantly high in advanced OSF (22). Activated form of T lymphocytes do not even generate cytokines of the fibrogenic variant that effects straight on connective tissue cells, and as well bring forth additional cytokines which activates macrophages for the secretion of fibrotic cytokines which moderate the purpose of mesenchymal cells implicitly (23). This can be related to the study done on inflammatory cells induced cytokines and growth factors which might endorse fibrosis by persuading propagation of fibroblasts (FBs), upregulation in synthesis of collagen, and downregulation of collagenase synthesis (22). Both the studies by Chiang et al. and Haque et al. presented augmented amount of T lymphocytes and macrophages activated form in the oral mucosal subepithelial portion of affected OSF cases. Captivating such outcomes altogether, can be accomplished about the cellular immune event with the raised formation of fibrogenic cytokines and decrease in antifibrotic cytokines that plays majorly in the OSF pathogenesis suggesting the higher density of T lymphocytes of epithelium in the OSF specimens compared to normal (22,23).

A higher level of phenotypic allele A6 of MHC class I chain-related gene A (MICA) in OSF is concomitant to the variation in T-cell action (24). Few genotypes of cytotoxic T-lymphocyte associated antigen 4 (CTLA-4), which is negative regulator of T-lymphocyte activating factor appears to take a vulnerability for several autoimmunity which could be correlated with the OSF. Remarkably, the allele G at location +49 of exon 1 were instituted to be related with OSF related to controls (25). The CD68 in the affected cases of a moderate and advanced type of OSF was found high that of the controls with statistical significance. Which advocates that CD68 has a major part in OSF pathogenesis and could be observed as a major biomarker for evaluating the prognosis (26).

The study by Wang et al. on FBs by cytokine-containing supernatant which was co-cultured with human peripheral blood mononuclear cells (PBMCs), the cytometric analysis gave increase in Th17, but significant decrease in Treg. The arecoline may alter inflammatory cytokines given by FBs, which in turn show upon immune cells Th17 and Treg, and alteration is seen (27). The studies pertaining to T cell and OSF are listed down in Table 1.

T cell in OSCC with a background in OSF

OSCC arising in OSF make up a clinicopathologically outlined entity, the variances of that supposed to rise from disparity in the pathogenesis of areca nut carcinogenesis. Various studies were done on OSF about T cells and their subsets show the increase in the infiltration or the density of T cells depending on the various grades of OSF suggesting the disparity of immunoregulation and variation in tissue architecture locally and also inflammatory cells activate certain cytokines which are responsible for tissue fibrosis in OSF. The T lymphocytes and macrophages in active form affect the host immune cellular retort with the raised secretion of fibrogenic cytokines and reduction of antifibrotic cytokines with key pathogenesis factor of OSF (21-23).

Sarode et al. hypothesized about the MT of OSF, transforming epithelial malignant cells might hold the genetic memory of earlier distinction and maturation ensuing in a better tumor differentiation stage (28). Silva et al. studied the immature dendritic cells (DCs), Langerhans’ cells, and plasmacytoid DCs organization which recognize antigens and present to T cells in OSF, OSF-related with OSCC, and other OPMDs. They showed immunoreactivity was lower in positive CD1a and CD207 cells in both the entities of OSF and OSCC-OSF considered with comparison to the standard epithelium (5) (Table 1). The countenance in receptor CD207 in DCs signals the antigen is efficiently joined with MHC-I and MHC-II, a form that triggers the CD8⁺ and CD4⁺ T cells; so, this down-regulated receptor in DCs may designate a conquest of the response of T-cell. A steady upsurge in CD303⁺ cells was detected for all the lesions of the study group. This increased value of CD303⁺ cells may be connected to the defense part of the immune system. The decreased number of cells CD1a⁺ and CD207⁺ can subordinate in the growth of OSCC, and in OPMDs which will be pointers of prognosis to malignancy. This indicated about areca nut consumption might yield a more suppressing immune cell role (5).

Conclusions

Looking at the above studies, it can be understood that immunosurveillance and immune cells play a significant role in the development of the OSF and OSCC. It can be advisable that assessing of OSF and cancer patients immunologically might give up early diagnosis and/or prognosis. The response of host immune T cells with their subsets creates great prognostic value as immune defense, especially in OSF, and can be considered as markers in malignant transformers which may be valuable for proactive intervention, particularly in high-risk groups. More studies can be undertaken to know in-depth pathogenesis and related pathways about T cells and OPMD. Taking this review as background it can be hypothesized that their can be essential role of T cell subsets in OSF and OSCC in background of OSF and in detail T cell profiling can prove the prognostic value.

Acknowledgments

Funding: None.

Footnote

Peer Review File: Available at https://fomm.amegroups.com/article/view/10.21037/fomm-23-5/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://fomm.amegroups.com/article/view/10.21037/fomm-23-5/coif). The authors have no conflicts of interest to declare.

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