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ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 3  |  Page : 625-630

Impact of stromal CD45RO+ immune cells on proliferation and dedifferentiation in node-negative squamous cell carcinomas of cheek mucosa


1 Department of Oral Pathology and Microbiology, Subharti Dental College and Hospital, Meerut, Uttar Pradesh, India
2 Consultant Oral and Maxillofacial Pathologist, Smile Square Multispeciality Dental Center, Karur, Tamil Nadu, India

Date of Web Publication29-May-2019

Correspondence Address:
Dr. Arvind Venkatesh
Smile Square Multispeciality Dental Center, 20/116, Dindigul Road, Karur - 639 001, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_263_16

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 > Abstract 


Background: The most fundamental trait of cancer cells involves their ability to sustain chronic proliferation. Tumors have a complex cellular ecology that establishes the malignant potential of the tumor. In these ecosystems, innate immune cells are highly represented. Many contradictory reports have been published regarding the impact of tumor-infiltrating immune cells on proliferation of the tumors.
Aim: This study aims to assess the impact of CD45RO+ve immune cells on proliferation and dedifferentiation of node-negative squamous cell carcinomas of cheek mucosa (SCC-CM).
Materials and Methods: Thirty formalin-fixed paraffin-embedded tissue blocks of previously diagnosed node-negative SCC-CM subclassified as Grade I SCC – 10 cases; Grade II SCC – 10 cases; and Grade III SCC – 10 cases (Broders' classification – 1927). Immunohistochemistry performed on each selected tissue section using anti-p53 and anti-CD45RO as primary antibodies. Semi-quantitative analyses performed for all the tissue sections to assess the p53 and CD45RO expression. p53:CD45RO expression ratio calculated. The data were statistically analyzed using GraphPad Prism 5 for Windows.
Results: Our results showed statistically significant increase (P = 0.0006) in p53 expression and decrease (P = 0.0044) in CD45RO+ immune cell response with the decrease in differentiation of SCC-CMs using Fisher's exact test and statistically significant increase (P < 0.001) in p53:CD45RO expression ratio with decrease in differentiation using one-way ANOVA.
Conclusion: Based on all these findings from the present study, we perceive the following findings. In node-negative SCC-CMs, CD45RO+ immune cells play a possible role in controlling the dedifferentiation of the tumor and in limiting the proliferative potential of the tumor cells which are tumor antagonistic in nature.

Keywords: CD45RO, dedifferentiation, immune response, p53, proliferation, proliferation, squamous cell carcinoma


How to cite this article:
Wadhwan V, Venkatesh A, Aggarwal P, Reddy V, Sharma P, Palakshappa SG. Impact of stromal CD45RO+ immune cells on proliferation and dedifferentiation in node-negative squamous cell carcinomas of cheek mucosa. J Can Res Ther 2019;15:625-30

How to cite this URL:
Wadhwan V, Venkatesh A, Aggarwal P, Reddy V, Sharma P, Palakshappa SG. Impact of stromal CD45RO+ immune cells on proliferation and dedifferentiation in node-negative squamous cell carcinomas of cheek mucosa. J Can Res Ther [serial online] 2019 [cited 2019 Dec 7];15:625-30. Available from: http://www.cancerjournal.net/text.asp?2019/15/3/625/243487




 > Introduction Top


The biological capabilities acquired during the multistep development of human tumors are referred to as hallmarks of cancer.[1] They include sustaining proliferative signaling, evading growth suppressors, resisting cell death, enabling replicative immortality, inducing angiogenesis, activating invasion and metastasis, reprogramming of energy metabolism, and evading immune destruction.[1],[2]

The most fundamental trait of cancer cells involves their ability to sustain chronic proliferation. In addition, cancer cells must also circumvent powerful programs that negatively regulate cell proliferation; many of these programs depend on the actions of tumor suppressor genes.[3] One of the prototypical tumor suppressors encode the TP53 proteins; they operate as central control nodes within two key complementary cellular regulatory circuits that govern the decisions of cells to proliferate or, alternatively, activate senescence and apoptotic programs.[4]

Tumors have a complex cellular ecology that establishes the malignant potential of the tumor. In these ecosystems, innate immune cells are highly represented.[5] The stroma in human carcinomas consists of extracellular matrix and various types of noncarcinoma cells, mainly leukocytes, endothelial cells, fibroblasts, myofibroblasts, and bone marrow-derived progenitors.[6] Immune cells are represented by those of innate immunity, including macrophages, neutrophils, mast cells, myeloid-derived suppressor cells, dendritic cells and natural killer cells, and cells of adaptive immunity, such as T- and B-lymphocytes.[7] CD45 is known as the leukocyte common antigen. It functions as a tyrosine phosphatase in leukocyte signaling. CD45RO is a marker for memory cells – expressed when naive CD45 leukocyte antigen changes into an activated isoform.[8]

Many contradictory reports have been published regarding the impact of tumor-infiltrating immune cells on tumors. The primary reason for these contradictory observations and the molecular mechanism(s) for the reported diverse impacts, however, have not been elucidated.[9],[10],[11],[12] It has long been speculated that these contradictory reports may result from differences in tissue types and tumor stages, in which infiltrating immune cells are differently distributed and physically associated with different cell types.[13]

Hence, we intended to assess the impact of CD45RO+ve immune cells on proliferation and dedifferentiation of node-negative squamous cell carcinomas of cheek mucosa (SCC-CM).


 > Materials and Methods Top


After institutional review board approval, paraffin-embedded tissue blocks of 30 previously diagnosed cases of SCC-CM were retrieved from pathology archives. Fresh hematoxylin and eosin-stained sections were made of all the cases retrieved and histopathological interpretation was done by three qualified pathologists (V. W., P. A., and V. R.) to confirm the grading of SCC as per Broders' classification (1927). The final study material included Grade I SCC – 10 cases; Grade II SCC – 10 cases; and Grade III SCC – 10 cases. The following inclusion and exclusion criteria were considered during the selection of cases.

Inclusion criteria

  1. Histopathologically confirmed cases of squamous cell carcinomas (8070/3) of cheek mucosa (C 06.0)
  2. Cases with complete clinical history and TNM staging
  3. Adequate availability of paraffin-embedded tissue blocks.


Exclusion criteria

  1. Patients with SCCs other than from cheek mucosa
  2. Unavailability of clinical or pathological TNM data
  3. Cases with positive nodes, perineural invasion, distant metastasis, and extracapsular spread
  4. Patients suffering with other diseases such as blood dyscrasias, autoimmune, immunodeficiency diseases, or any systemic disease affecting normal immune response
  5. Administration of chemotherapy or radiotherapy before the biopsy procedure.


Immunohistochemistry

From each paraffin-embedded tissue block selected, consecutive serial sections of 3 μm thicknesses were made on two poly-l-lysine-coated slides. Sections were deparaffinized and rehydrated with xylene and serial dilutions of ethanol to distilled water. Tissue sections were immersed in 1× sodium citrate buffer at a pH of 6 and heat-induced epitome retrieval was done using autoclave method at 120°C; 12–15 psi for 15 min. For each sample, anti-p53 antibody (Biogenex, Fremont, USA, mouse IgG, ready to use) was used as primary antibody on tissue sections of one slide and anti-CD45RO antibody (Biogenex, Fremont, USA, mouse IgG, ready to use) on the other tissue sections for a 1-h incubation at room temperature in a humidity chamber. The antigen-antibody binding was detected with labeled antimouse polymer-HRP detection system and DAB + chromogen (Biogenex, Fremont, USA). Tissue sections were briefly immersed in hematoxylin for counterstaining. In all cases, staining of dysplastic epithelial cells served as positive internal controls for anti-p53 antibody and sections of tonsils with known antigenic potential were used as positive controls for anti-CD45RO antibody. For negative control, the primary antibody was replaced by mouse-negative control (nonimmune serum in phosphate-buffered saline with 0.09% sodium azide).

Semi-quantitative assessment and statistical analysis

The slides were initially analyzed at low magnification (×100) to select the areas to be included for semi-quantitative assessment [Figure 1]. p53 expression was analyzed in the cancer islands which were defined as cancer tissue without fibroblasts and vasculature. Five high-power fields (×400) were selected in tumor proper area and the percentage of immunoreactive dysplastic cells were categorized based on the scores as mentioned in [Table 1]. CD45RO expression was analyzed in the stroma which was defined as connective tissue surrounding cancer nests without any cancer cells. Five high-power fields (×400) surrounding the dysplastic islands assessed for p53 expression and based on the type or pattern of CD45RO positive immune cells in the stroma, a specific score was assigned as mentioned in [Table 2].
Figure 1: Selection of areas for semi-quantitative assessment (original magnification ×100)

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Table 1: Scoring criteria for p53 expression

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Table 2: Scoring criteria for CD45RO expression

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p53 expression in squamous cell carcinomas of cheek mucosa

Various staining patterns were observed for p63 expression in SCC-CMs [Table 3]. It was observed that the pattern of staining differs between the grading of neoplasms. Grade I neoplasms showed a uniform staining pattern with the percentage of positive cells generally <50% (7/10) [Figure 2]a of the dysplastic epithelial cells in the stroma. Few (3/10) showed increased expression (50%–75%). Among Grade II neoplasms, the expression of p53 increased and most of the cases (7/10) showed >50% [Figure 3]a of p53-positive dysplastic epithelial cells. Grade III neoplasms showed highest percentage of expression with majority of the cases (9/10) showing the highest degree of p53 expression (>75%) [Figure 4]a. In both Grade II and III, the pattern of expression was more intense and diffuse compared to the Grade I counterparts. Staining for p53 was not detected in the keratin pearl areas. Hence, in SCC-CM, both low and high p53 percentage of positive cell could be appreciated by p53 immunolabeling, having more positive cells in less differentiated tumors than in highly differentiated ones.
Table 3: p53 expression scores in various grades of squamous cell carcinoma-cheek mucosa

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Figure 2: (a) p53 expression in Grade I squamous cell carcinomas (original magnification ×400). (b) CD45RO expression in Grade I squamous cell carcinomas (original magnification ×400)

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Figure 3: (a) p53 expression in Grade II squamous cell carcinomas (original magnification ×400). (b) CD45RO expression in Grade II squamous cell carcinomas (original magnification ×400)

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Figure 4: (a) p53 expression in Grade III squamous cell carcinomas (original magnification ×400). (b) CD45RO expression in Grade III squamous cell carcinomas (original magnification ×400)

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CD45RO expression in squamous cell carcinomas of cheek mucosa

Various staining patterns and types of distribution were observed in the CD45RO+ immune cells in the stroma [Table 4]. Similar to p53 expression, it was observed that there was a grade-dependent alteration in the pattern and intensity of CD45RO+ immune cells in the stroma. Grade I neoplasms showed mainly, dense pattern (continuous/discontinuous) (9/10) of CD45RO+ immune cells in the stroma [Figure 2]b. One case of Grade I neoplasm showed sparse CD45RO+ immune response. Grade II neoplasms showed a wide range of CD45RO+ immune expression with cases showing both dense (6/10) and diffuse [Figure 3]b or limited (4/10) patterns of immune response. Grade III neoplasms showed generally decreased immune response. All the cases (10/10) showed sparse (5/10) [Figure 4]b or limited (5/10) CD45RO+ immune response. Hence, in SCC-CM cases, dense, diffuse, and limited percentage of positive cells in the stroma could be detected by CD45RO immunolabeling, have more positive expression in well-differentiated tumors than the less differentiated ones.
Table 4: CD45RO expression scores in various grades of squamous cell carcinoma-cheek mucosa

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p53:CD45RO expression score in squamous cell carcinomas of cheek mucosa

p53:CD45RO expression score was calculated across the groups [Table 5] which showed increase in the p53:CD45RO ratio from Grade I to Grade III neoplasms. Although overlapping ratios were observed between Grades I and II and II and III, the means of score ratio were ascending from Grade I (mean, x = 0.625) through Grade II (mean, x = 1.175) to Grade III (mean, x = 2.9) neoplasms. This is in consensus with the increase in p53 and decrease in CD45RO immunolabeling from highly differentiated to undifferentiated tumors.
Table 5: p53:CD45RO score ratio in various grades of squamous cell carcinoma-cheek mucosa

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 > Statistical Analysis and Results Top


The data were statistically analyzed using GraphPad Prism 5.03 for Windows (GraphPad Software Inc., La Jolla, CA, USA). A statistically significant correlation (P = 0.0006) has been found between p53 expression and the histological grading of the tumor when we evaluated the p53 expression and the grading of the tumor by Fisher exact test [Table 3]. In fact, the percentage of cells expressing p53 was lower in well-differentiated tumors with respect to undifferentiated ones.

Similarly, a statistically significant correlation (P = 0.0044) has been found between CD45RO expression and the histological grading of the tumor when we evaluated the CD45RO expression and the grading of tumor by Fisher exact test [Table 4]. In contrast with p53 expression, the density of CD45RO+ immune cell pattern was higher in well-differentiated tumors with respect to undifferentiated ones.

One-way ANOVA showed significant increase (<0.001) in the p53:CD45RO score ratio from Grade I to Grade III neoplasms [Table 5] and Tukey's multiple comparison posttest revealed statistically significant increase (P < 0.05) in the p53:CD45RO score ratio between SCC-CMs of Grades II–III and I–III.


 > Discussion Top


In most studies performed, squamous cell carcinomas of head and neck (SCCHN) from all different subsites are included and results interpreted as valid for the whole group of SCCHN tumors. A study conducted by Boldrup et al.[14] showed a distinct difference between normal tissues from different subsites, emphasizing the fact that SCCHN comprises a heterogeneous group of tumors that should be analyzed based on subsite. Hence, in the present study, squamous cell carcinomas (8070/3) of cheek mucosa (C 06.0)[15] alone were included to avoid bias due to subsite.

A characteristic of cancer cells is its ability to undergo extensive proliferation through overproducing growth factors. The tumor suppressor gene (p53) is a negative regulator of cell cycle progression.[16] Various studies have shown positive correlation between p53 expression and degree of differentiation and proliferation of the tumor.[17],[18]

Pathological evidence has continually supported the prognostic value of tumor-infiltrating T-lymphocytes for several solid tumors across diverse patient cohorts. Numerous markers including CD3, CD4, CD8, CD16, CD45, CD68, CD134, and Tregs (CD4+Foxp3+)[19] have been employed alone and/or in combinations in literature to analyze the immune response in various tumors. However, T-cells expressing CD45RO, which is the most suitable single marker of human memory T-cells, have been demonstrated to play specific and significant roles in a number of human cancers such as colorectal cancer, gastric cancer, esophageal carcinoma, and ovarian and renal cell carcinoma.[20],[21],[22],[23],[24],[25],[26] Moreover, a meta-analysis conducted on this regard has showed that intratumor infiltration by CD45RO+ memory T-cells is a robust immunological indicator of a favorable survival time in cancer patients and that CD45RO is more sensitive than CD3 for categorizing patients, based on the clinical outcomes. The predictive significance of memory tumor-infiltrating lymphocytes (TILs) was reproducible among cohorts with diverse tumor types, regardless of the detailed characteristics of the patients.[27] Hence, CD45RO was our choice of immune cell marker in the present study.

Currently, there are two concepts regarding the search for carcinoma cells by the immune system. Immune surveillance is based on the specific identification of transformed and normal cells through their different antigenic determinants. The Erhlich–Thomas–Burnet theory of immune surveillance considers that the immune system protects against transformed cells carrying foreign, nonself signals, whereas the Grossman–Heberman theory proposes an antitumor surveillance system that regulates self-population of cells.[28],[29],[30]

Although the precise nature of the immune system's role in cancer has not been fully elucidated, we know that tumors are immunogenic and that cancer is caused by a variety of genetic defects that occur in genes that encode for proteins involved in cell growth.[31] The components of the immune system, antibodies, and T-cells do not recognize or respond to defective genes but recognize and respond to the abnormal proteins the cancer-causing genes encode. Thus, the individual components of the immune system play a major role in cancer.[32]

Various contrasting results have been obtained in studies conducted regarding the impact of tumor-infiltrating immune cells on tumors. On the one hand, certain studies have reported that direct physical contact between infiltrating immune cells and tumor cells is associated with the destruction of associated tumor cells, reduction of tumor size, and significantly improved clinical prognosis.[9],[10] On the other hand, a steadily increasing number of publications have shown that increased immune cell infiltration promotes tumor progression and invasion.[11],[12] It has long been speculated that these contradictory reports may result from differences in tissue types and tumor stages, in which infiltrating immune cells are differently distributed and physically associated with different cell types.[13]

From the present study, in addition to statistically significant increase (P = 0.0006) in p53 expression and decrease (P = 0.0044) in CD45RO+ immune cell response with the decrease in differentiation, certain interesting findings have also been discerned. The p53:CD45RO score ratio showed statistically significant (P < 0.001) increase in the ratio with decrease in differentiation.

Furthermore, when the study population was tabulated based on the p53 expression [Table 6], certain findings were evident.
Table 6: p53 score of various grades of squamous cell carcinoma-cheek mucosas and corresponding mean CD45RO score

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  1. Decrease in the mean CD45RO score with decrease in differentiation among cases with the same p53 score
  2. Among cases of same grades, increase in the mean CD45RO score was appreciated with increase in the p53 scores.


Based on all these findings from the present study, we perceive the following findings. In node-negative SCC-CMs, CD45RO+ immune cells play a possible role in

  1. Controlling the dedifferentiation of the tumor
  2. Limiting the proliferative potential of the tumor cells.


There are numerous complex mechanisms which are involved in generation and storage of tumor-specific immune cells in humans which include tumor antigen density, tumor environments, cytokine generation, cellular apoptosis, and other regulatory functions on TILs.[33] Immunoregulatory pathways like Fas/FasL have also been reported to be involved in tumor-specific immune generation in esophageal cancers.[34] This indicates that immune cells can generally recognize and respond to endogenous cancer cells and metastases/disease progression occurs only when immune response is unable to contain tumor progression.

Absence of unique tumor antigens, downregulation of target antigens, absence of adhesion molecule expression, and secretion of immunosuppressive cytokines have been the proposed reasons for immune evasion which is considered to be the possible reason of invasion and metastasis.[35]

The present study is unique since it is the first of its kind to assess the combined p53 and CD45RO+ immune response in SCCHN patients. The results of the study are congruent with the results of equivalent studies conducted on various types of cancers.[20],[21],[22],[23],[24],[25],[26] Hence, in node-negative SCC-CMs, immune cells are tumor antagonizing in nature.

Since we had not included node-positive cases, the role of CD45RO+ cells in metastasis could not be analyzed from the present study.

Future perspectives

We intend to extend the present study by assessing combined p53 and CD45RO expression at the epithelium-connective tissue interface and invasive front region of SCCHNs and thereby comparing the expression ratio with the results of the present study. Thereby, we wish to analyze the differences in the p53:CD45RO score ratio at different sites of the tumor which might throw more light on the role of immune cells at various points of progression of the tumor. Moreover, the study would be extended by including cases with nodal and regional metastases.

Clinical and therapeutic implications

Tumor-infiltrating CD45RO+ cells may materially improve patient outcome,[19] hence it can be used as an prognostic biomarker. The present study supports the applicability of p53:CD45RO expression as a prognostic biomarker for SCC-CM candidates.

Quantification of memory T-lymphocytes in a tumor site could provide feasible criteria for patient selection in clinical trials aimed at evaluating the efficacy of immunotherapy. Enhancement of the quantity and quality of memory TILs in situ may provide a novel strategy to improve the prognosis of cancer patients.[35]


 > Conclusion Top


In summary, p53:CD45RO ratio is significantly associated with significant lesser dedifferentiation and proliferation of the SCC-CMs independent of the clinical features. Our findings suggest that tumor-infiltrating CD45RO+ cells may materially improve patient outcome, offer a possible mechanism conferring an improved patient outcome, and support efforts to augment the host immune response as a therapeutic strategy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

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