Tumor-infiltrating T cells as a risk factor for lymph node metastasis in patients with submucosal colorectal cancer

doi:10.21203/rs.3.rs-2106382/v1

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Tumor-infiltrating T cells as a risk factor for lymph node metastasis in patients with submucosal colorectal cancer

https://doi.org/10.21203/rs.3.rs-2106382/v1

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published 06 Feb, 2023

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Approximately 10% of patients with colorectal cancer with submucosal invasion have lymph node metastasis. Pathological risk factors for lymph node metastasis have varying sensitivities and specificities. To predict the risk of lymph node metastasis, the identification of new risk factors is vital. Tumor-infiltrating T cells have been reported to improve the prognosis of many solid tumors. Therefore, the purpose of this study was to examine the relationship between lymph node metastasis and tumor-infiltrating T cells in patients with colorectal cancer with submucosal invasion. We examined CD8⁺ tumor-infiltrating T cells level as a risk factor for lymph node metastasis in patients with colorectal cancer with submucosal invasion and showed that low CD8⁺ tumor-infiltrating T cells levels are positively correlated with lymph node metastasis. Furthermore, by combining the number of CD8⁺ and CD103⁺ tumor-infiltrating T cells, the results showed a high positive predictive value for lymph node metastasis in cases with low numbers of both types of tumor-infiltrating T cells and a high negative predictive value in cases with high numbers of both types of tumor-infiltrating T cells, indicating that we were likely able to validate an effective subset of CD8 T cells.

submucosal invasion

lymph node metastasis

TILs

CD8

CD103

Approximately 10% of patients with colorectal cancer with submucosal invasion (SM-CRC) experience lymph node metastasis. For such patients, the Japanese Society for Cancer of the Colon and Rectum guidelines recommend surgical resection with lymph node dissection.^[1]

For patients diagnosed with SM colorectal cancer after endoscopic treatment, additional surgical resection is performed based on pathological findings. The guidelines recommend additional resection in cases with one or more of the following pathologic factors related to lymph node metastasis: depth of submucosal invasion greater than 1000 µm, positive lymphovascular invasion, positive endoscopic vertical margin, poorly differentiated adenocarcinoma, signet-ring cell carcinoma, or mucinous carcinoma, and grade 2/3 budding at the site of the deepest invasion.^[1] These pathological risk factors for lymph node metastasis have varying sensitivities and specificities. For example, a depth of submucosal invasion ≥ 1000 µm has a sensitivity of 94.8% and specificity of 19.0% for positive lymph node metastasis, while an undifferentiated histological type has a sensitivity of 13.3% and specificity of 97.9%.^[2] The combination of these risk factors results in lymph node risks ranging from 7.4 to 46.9% in patients with SM-CRC.^[3] Therefore, to predict the risk of lymph node metastasis, various methods, such as nomograms, have been utilized.^[4]

The identification of new risk factors for lymph node metastasis in patients with SM-CRC is crucial.^{[5, 6]} In recent years, cancer immunity has been one of the most important factors associated with tumor prognosis,^[6] and tumor-infiltrating T cells (TILs) have been reported to improve the prognosis of many solid tumors.^[7] T cells can be classified as CD8⁺ or CD4⁺ T cells.^[8] CD8⁺ T cells are cytotoxic T cells that contribute significantly to tumor prognosis.^[9] Nevertheless, the role of CD8⁺ TILs in predicting lymph node metastasis in patients with SM-CRC has not been well evaluated. Although TILs in colorectal cancer have prognostic value,^[10] the relationship between TILs and lymph node metastasis in patients with SM-CRC has not been reported.

Recently, CD103⁺ CD8⁺ T cells have been found to play an important role in cancer immunity, particularly in cancers of epithelial origin.^[11]

The ligand for CD103 is the epithelial cell surface molecule E-cadherin, an epithelial-mesenchymal transition (EMT) marker.^[12] Loss of E-cadherin in tumors is the hallmark of EMT and has been reported to be associated with poor prognosis for patients with colorectal cancer.^[13–15] Therefore, we hypothesized that the number of infiltrating CD103⁺ cells is indirectly related to the EMT of the tumor and examined the relationship between the number of CD103⁺ TILs and lymph node metastasis.

Thus, the purpose of this study was to examine the relationship between lymph node metastasis and TILs in patients with SM-CRC. By quantifying the number of CD8⁺ TILs in this study, we found for the first time that the risk of lymph node metastasis was low in patients with high CD8⁺ TIL density, and CD8⁺ TIL density had a higher negative predictive value (NPV) for lymph node metastasis than other risk factors. Furthermore, the number of CD103⁺ TILs was evaluated in the same way. The number of infiltrating CD103⁺ CD8⁺ T cells had a high NPV and positive predictive value (PPV).

We identified CD8⁺ T cells in surgically resected specimens from patients with SM-CRC using immunohistochemical staining with CD103 and CD8 antibodies. Of the total 180 eligible patients enrolled in this study, 15 patients treated with local excision that lacked lymph node dissection data and 67 patients without available tumor tissue were excluded. Finally, CD8 + TILs were evaluated in 98 cases (Fig. 1).

The evaluation site of the lymphocytes is shown in Fig. 2a. As shown in the figure, the invasive margin was set up, and the deepest part of the invasive margin with a large amount of tumor epithelial tissue was evaluated at ×200 magnification. Immunohistochemical staining showed variation among cases in the number of CD8⁺ TILs (Fig. 2b).

The characteristics of the 98 patients are presented in Table 1. Only two cases displayed undifferentiated histology, and lymph node metastasis was observed in 11 patients (11.2%). The median number of CD8⁺ TILs was 185 in 10 high-power fields (HPFs).

Table 1

Clinicopathologic factors of all patients
Factor	N = 98
Age, median (years)	66 (35–86)
Sex [male/female]	58/40
Location [colon/rectum]	63/35
Histological type [tub1/tub2/por, muc]	53/43/2
Greatest diameter, median (mm)	20 (3–66)
Depth of invasion, median (µm)	2700 (100–35000)
Lymphatic invasion [+/-]	27/71
Vascular invasion [+/-]	16/82
Budding grade [1/2/3/NA]	71/13/3/11
Preoperative CEA, median (ng/ml)	2 (0–21)
Preoperative CA19-9, median (ng/ml)	9 (0–243)
Number of CD8⁺ TILs (/10 HPF)	183 (10–1042)
CEA, carcinoembryonic antigen; CA19-9, Carbohydrate Antigen 19 − 9; CD, cluster of differentiation; TIL, tumor-infiltrating lymphocytes; HPS, high-power fields

The number of CD8⁺ TILs decreased as the number of lymph node metastases increased (Fig. 3a), with the exception of one case with three lymph node metastases and a high number of CD8⁺ TILs.

The number of CD8⁺ TILs was significantly higher in cases without lymph node metastasis (median: 180/10 HPF, range 10–1042) than in those with lymph node metastasis (median: 42/10 HPF, range 15–394; p = 0.042; Fig. 3b).

The relationship between the specificity and sensitivity of the number of CD8⁺ TILs for the purpose of lymph node metastasis is represented by a receiver operating characteristic (ROC) curve (Fig. 4). The area under the ROC curve (AUC) was 0.689 for the number of CD8⁺ TILs.

The number of CD8⁺ TILs with the cutoff value identified by ROC curve analysis was compared with other clinicopathological risk factors for lymph node metastasis in univariate and multivariate analyses. Univariate analysis revealed that lymphatic invasion (+), budding grade (3), and CD8⁺ TILs (low) were risk factors for lymph node metastasis. Multivariate analysis confirmed that lymphatic invasion (+) and the number of CD8⁺ TILs (low) were independent risk factors for lymph node metastasis.

The sensitivity, specificity, PPV, and NPV of each risk factor in the present dataset are shown in Table 2.

Table 2

Variables of lymph node metastasis (univariate and multivariate analyses)
	Univariate			Multivariate
Variable	OR	95% CI	p-value	OR	95% CI	p-value
Age ( ≧ 65 years)	1.09	0.31–3.85	0.890
Sex (female)	1.23	0.35–4.37	0.740
Location (rectum)	1.03	0.28–3.80	0.962
Histological type (por, muc)	-	-	-
Histological type (tub2, por, muc)	1.48	0.41–5.21	0.544
Greatest diameter ( ≧ 20 mm)	1.89	0.46–7.79	0.381
Depth of invasion ( ≧ 1000 µm)	2.15	0.25–18.2	0.483
Lymphatic invasion (+)	41.2	4.93–344	< 0.001	63.2	4.61–866	0.002
Vascular invasion (+)	1.16	0.23–5.95	0.860
Budding grade (2, 3)	1.82	0.42–7.79	0.421
Budding grade (3)	16.7	1.37–203	0.027	20.7	0.07–6523	0.302
Preoperative CEA ( ≧ 2 ng/ml)	2.75	0.55–13.8	0.219
Preoperative CA19-9 ( ≧ 10 ng/ml)	1.54	0.40–5.87	0.529
The number of CD8⁺ TILs ( ≦ 42/10 HPF)	10.4	2.64–41.0	< 0.001	16.9	1.46–195	0.024
OR, odds ratio; CI, confidence interval; CEA, carcinoembryonic antigen; CA19-9, Carbohydrate Antigen 19 − 9; CD, cluster of differentiation; TIL, tumor-infiltrating lymphocytes; HPF, high-power fields

To identify a better indicator of lymph node metastasis, we evaluated the presence of CD103, another T cell activation marker.

In the present study, we evaluated whether the combination of the number of CD8⁺ and CD103⁺ TILs could be a more accurate risk factor for lymph node metastasis.

Immunohistochemical staining showed that the number of CD103⁺ TILs varied among cases (Fig. 5a). The median number of CD103⁺ TILs was 116/10 HPFs. Furthermore, the number of CD103⁺ TILs was correlated with the number of CD8⁺ TILs (r = 0.524, p < 0.001).

The number of CD103⁺ TILs decreased as the number of lymph node metastases increased (Fig. 5b), except for one case with three lymph node metastases and a high number of CD103⁺ TILs. Moreover, the number of CD103⁺ TILs tended to be low in patients with lymph node metastasis; however, the difference was not statistically significant (p = 0.314; Fig. 5c). The AUC for the number of CD103⁺ TILs was 0.640 (Fig. 6).

The number of CD103⁺ TILs with the cutoff value identified by ROC curve analysis was compared with other clinicopathological risk factors for lymph node metastasis in univariate and multivariate analyses (Table 3). Univariate and multivariate analyses confirmed that CD103⁺ TILs (low) were an independent risk factor for lymph node metastasis.

Table 3

Factors evaluated for lymph node metastasis (univariate and multivariate analyses).
Lymph node metastasis	Univariate			Multivariate
Variables	OR	95% CI	p-value	OR	95% CI	p-value
Age ( ≧ 65 year-old)	1.09	0.31–3.85	0.890
Sex (Female)	1.23	0.35–4.37	0.740
Location (Rectum)	1.03	0.28–3.80	0.962
Histological type (por, muc)	-	-	-
Histological type (tub2, por, muc)	1.48	0.41–5.21	0.544
Greatest Diameter ( ≧ 20 mm)	1.89	0.46–7.79	0.381
Depth of invasion ( ≧ 1000 µm)	2.15	0.25–18.2	0.483
Lymphatic invasion (+)	41.2	4.93–344	< 0.001	50.1	4.97–504	< 0.001
Vascular invasion (+)	1.16	0.23–5.95	0.860
Budding Grade (2, 3)	1.82	0.42–7.79	0.421
Budding Grade (3)	16.7	1.37–203	0.027	11.6	0.05–2494	0.372
Preoperative CEA ( ≧ 2 ng/ml)	2.75	0.55–13.8	0.219
Preoperative CA19-9 ( ≧ 10 ng/ml)	1.54	0.40–5.87	0.529
The number of CD8⁺ TILs (< 46/10HPF)	10.4	2.64–41.0	< 0.001
The number of CD103⁺ TILs (< 52/10HPF)	5.32	1.44–19.6	0.012	6.58	1.00–43.3	0.049
OR, odds ratio; CI, confidence interval; CEA, carcinoembryonic antigen; CA19-9, Carbohydrate Antigen 19 − 9; CD, cluster of differentiation; TIL, tumor-infiltrating lymphocytes; HPS, high-power fields

Clinicopathological risk factors for lymph node metastasis and the number of CD8⁺ TILs, CD103⁺ TILs, and CD8⁺ CD103⁺ TILs were compared using sensitivity, specificity, PPV, and NPV.

The NPVs of CD8⁺ TILs and CD103⁺ TILs were higher than those of other risk factors, except for lymphatic invasion (Table 4). The PPV of CD8⁺ CD103⁺ TILs was also higher than that of other risk factors, suggesting that evaluating the numbers of CD8⁺ and CD103⁺ TILs was a better indicator than evaluating only CD8⁺ TILs (Table 4).

Table 4

Sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of risk factors
	Sensitivity	Specificity	PPV	NPV
Histological type (por, muc)	0	97.7	0	88.5
Histological type (tub2, por, muc)	54.5	55.2	13.3	90.6
Depth of invasion ( ≧ 1000 µm)	90.9	16.1	12.7	93.3
Lymphatic invasion (+)	90.9	80.5	37	98.6
Vascular invasion (+)	18.2	83.9	12.5	89
Budding grade (2, 3)	27.3	72.4	18.8	88.7
Budding grade (3)	18.2	86.2	66.7	89.3
CD8	54.5	89.7	40	94
CD103	54.5	81.6	27.3	93.4
CD8 and CD103 (LL/HH)	45.5	97.7	71.4	93.4
CD8 and CD103 (Other/HH)	63.6	73.6	23.3	94.1
CD, cluster of differentiation; LL, numbers of both CD103⁺ and CD8⁺ TILs were low; HH, numbers of both CD8⁺ and CD103⁺ TILs were high

In this study, we examined CD8⁺ TILs as a risk factor for lymph node metastasis in patients with SM-CRC. Our findings indicate low CD8⁺ TIL levels, as determined by the cutoff value from ROC curve analysis, to be a new, independent risk factor for lymph node metastasis. Furthermore, by combining the numbers of CD8⁺ and CD103⁺ TILs, we found a high PPV for lymph node metastasis in patients with low levels of both types of TILs and a high NPV in patients with high levels of both types of TILs. Thus, we most likely identified an effective subset of CD8⁺ T cells.

The few existing reports on the connection between TILs and lymph node metastasis have focused on breast cancer^[16] and melanoma.^[17] In these reports, low TIL density was associated with lymph node metastasis. In breast cancer, CD8⁺ TILs have been found to have a negative correlation with lymph node metastasis.¹⁸ Another study from 2020 reported a relationship between lymph node metastasis and TILs in early-stage breast cancer.¹⁶ Conversely, TIL density and lymph node metastasis have been reported to have a low correlation in patients with esophageal squamous cell carcinoma.¹⁹ One report has examined the relationship between TILs and lymph node metastasis in colorectal cancer; however, it examined CD3⁺ TILs and reported a low correlation,²⁰ likely because CD3⁺ cells include immunosuppressive T cells, such as Tregs.²¹ Tregs are involved in the development and progression of cancer by inhibiting anticancer immunity²² and express CD3, CD4, CD25, and Foxp3, but not CD8, which is a cytotoxic T-cell marker.²³ The number of tumor-infiltrating CD8⁺ T cells is associated with tumor prognosis in many solid tumors.²⁴ Therefore, we hypothesized that simultaneously evaluating Tregs and cytotoxic T cells may obscure the relationship between TILs and colorectal cancer lymph node metastasis; moreover, evaluating only cytotoxic T cells would better clarify the relationship between lymph node metastasis and TILs. In this study, we did not examine pan-T cell markers such as CD3 and CD4 but only evaluated markers of cytotoxic T cells such as CD8 and CD103. We focused on CD8 cytotoxic T cells and found a relationship between CD8⁺ TILs and lymph node metastasis.

Because tumors are heterogeneous, the site of assessment of the number of tumor-infiltrating T cells is important.²⁵ For example, previous reports have shown that the number of TILs in the tumor infiltrate is a more sensitive indicator of tumor metastasis than that in the center of the tumor.¹⁰ Therefore, in this study, we evaluated the TIL count at the tumor invasion site.

We further evaluated a subset of cytotoxic T cells that express CD103. CD103⁺ CD8⁺ T cells are associated with an epithelial-derived carcinoma prognosis¹¹ and CD103 alone contributes to prolonged survival in patients with bladder cancer,²⁶ ovarian cancer,²⁷ non-small cell lung cancer,²⁸ and melanoma.²⁹ Moreover, CD103 is expressed by the recognition of tumor antigens and is a marker of tumor-specific TILs.³⁰ However, in this study, CD103 alone was not a more accurate risk factor for lymph node metastasis than CD8. Additionally, this study featured only two cases of undifferentiated tumors, neither of which had lymph node metastasis. As CD103 was expected to predict lymph node metastasis to some extent, we would like to re-evaluate CD103 as a risk factor for lymph node metastasis by accumulating more cases.

The present study was single-centered and included only recent cases from 2014 to 2019, after budding was included as a risk factor for lymph node metastasis in cancer with submucosal invasion, according to the guidelines of the Japanese Society for Cancer of the Colon and Rectum. We included the 98 cases of SM-CRC at our hospital for whom resected pathological specimens were available. Additionally, 11 cases (11.2%) of lymph node metastasis were observed, which is consistent with previously established rates of lymph node metastasis in SM-CRC of approximately 10%. However, the small number of cases with lymph node metastasis is a limitation of this study, and future studies with more cases are warranted.

In conclusion, we examined CD8⁺ TIL levels as a risk factor for lymph node metastasis in patients with SM-CRC and showed that low CD8⁺ TIL levels are positively correlated with lymph node metastasis. The number of CD8⁺ TILs using a cutoff value identified by receiver operating characteristic curve analysis was an independent risk factor for lymph node metastasis.

This study was approved by the Research Ethics Committee of Osaka University (approval no. 17448). The study was conducted in accordance with the principles of the 1964 Declaration of Helsinki and its subsequent amendments, or equivalent ethical standards. Written informed consent was obtained from all patients.

Study design and patients

In this study, we evaluated 180 patients with SM-CRC who underwent surgical resection between 2014 and 2019 at Osaka University Hospital.

Immunohistochemical staining

Immunohistochemical staining was performed on formalin-fixed paraffin-embedded tissue sections (4.0 mm). After deparaffinization, antigen retrieval was performed using 10 mmol/L citrate buffer (pH 6), and intrinsic peroxidase activity was blocked using 3% H₂O₂ for 20 min, followed by nonspecific interaction blocking with a background sniper (Biocare Medical, Pacheco, CA, USA) for 10 min. Tissue sections were stained with anti-CD8 (ab75129, mouse, diluted 1:50) and CD103 (ab129202, rabbit, diluted 1:2,000) antibodies using the Vectastain ABC kit (Vector Laboratories, Burlingame, CA, USA). The number of CD8⁺ and CD103⁺ T cells in 10 HPFs at the tumor-invasive margins was counted using ImageJ software version 1.8.0 (NIH, Bethesda, MD, USA; http://imagej.nih.gov/ij).

Statistical analysis

Statistically significant differences between categorical variables were determined using the χ² test and between continuous variables using the Mann–Whitney test.

All statistical analyses were performed using R version 4.0.2 and JMPpro 14.0.0 (SAS Institute, Cary, NC, USA). Statistical significance was set at P < 0.05.

Acknowledgments: None.

Author Contributions: M. K., S. F., N. M., M. U., T. M., Y. D., and H. E. were involved in study design and data interpretation. M. K, S. F., N. M., Y. S., T. H., T. O., H. T., M. U., and T. M. were involved in the data collection and analysis. All authors critically revised the report, commented on drafts of the manuscript, and approved the final report.

Data availability: All relevant data were included in this report.

Competing Interests: The author(s) declare no competing interests.

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Tumor-infiltrating T cells as a risk factor for lymph node metastasis in patients with submucosal colorectal cancer

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