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. 2022 Nov 14;14(22):5573.
doi: 10.3390/cancers14225573.

Expression Pattern and Prognostic Value of CTLA-4, CD86, and Tumor-Infiltrating Lymphocytes in Rectal Cancer after Neoadjuvant Chemo(radio)therapy

Xin-Ke Yin  1 , Chao Wang  2   3 , Li-Li Feng  3   4 , Shao-Mei Bai  3 , Wei-Xing Feng  3   4 , Neng-Tai Ouyang  1 , Zhong-Hua Chu  5 , Xin-Juan Fan  2   3 , Qi-Yuan Qin  3   6
Affiliations

Expression Pattern and Prognostic Value of CTLA-4, CD86, and Tumor-Infiltrating Lymphocytes in Rectal Cancer after Neoadjuvant Chemo(radio)therapy

Xin-Ke Yin et al. Cancers (Basel). .

Abstract

The synergistic effect of combining immune checkpoint inhibitors (ICIs) with neoadjuvant chemo(radio)therapy (nCRT) in colorectal cancer is still limited. We aimed to understand the impact of nCRT on the tumor microenvironment and to explore favorable immune markers of this combination. Herein, we investigated the expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), CD86, CD4, and CD8 after nCRT and its association with clinicopathological characteristics. Immunostaining of immune-related molecules was performed in 255 surgically resected specimens from rectal cancer patients treated with nCRT. CD4 and CD8 expression on the tumor (tCD4/CD8), stroma (sCD4/CD8), and invasive front (iCD4/CD8) was evaluated. The expression levels of immune-related molecules were significantly lower in the nCRT-treated group, except for CTLA-4 and sCD8. However, patients with higher sCD8+ cell density and CTLA-4 expression had better progression-free survival (PFS) and distant metastasis-free survival (DMFS). In addition, higher CD86 expression was associated with poorer overall survival (OS). Higher CTLA-4 expression was associated with higher tCD8+ cell density, whereas CD86 expression was correlated with the cell density of t/sCD8. Prognostic analysis confirmed that the relationships between CTLA-4 and DMFS as well as CD86 and OS were significantly correlated in low rather than high CD8+ cell density. Further the combination of CD8+ cell density and CD86 expression was shown to be an independent prognostic factor of OS, whereas the combination of CTLA-4 was not for DMFS. Together, these results demonstrate significant correlations between CD86 expression and t/sCD8+ cell density in rectal cancer after nCRT and could potentially have clinical implications for combining ICIs and nCRT.

Keywords: immune checkpoint molecules; immunotherapy; neoadjuvant chemo(radio)therapy; rectal cancer; tumor-infiltrating lymphocytes.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Immunohistochemical staining of immune-related molecules. (A) CTLA-4+ cells were detected on the stroma and tumor. (B) The expression of CD86 was detected on the lymphocytes. (C–H) CD8 and CD4 positive cells were divided into tCD8+/tCD4+ cells (lymphocytes on the tumors, (C,D)), sCD8+/sCD4+ cells (lymphocytes on the stroma where the curve labeled, (E,F)), and iCD8+/iCD4+ cells (lymphocytes on the invasive front, (G,H)).
Figure 2
Figure 2
Expression of CTLA-4, CD86, CD4, and CD8 in rectal cancer after nCRT. (A) Schematics showing the workflow for detecting and quantifying the expression of immune-related molecules. (B) Paired t test was performed between s/t/iCD4+ and s/t/iCD8+ cells.
Figure 3
Figure 3
Kaplan-Meier curves and multivariate analysis of survival. (A) PFS according to the status of sCD8+ cell (low or high). (B) DMFS according to CTLA-4+ cell density (low or high). (C) OS according to CD86 expression (low or high) level. PFS, progression-free survival; DMFS, distant metastasis-free survival; OS, overall survival. (D–F) Forest plots of PFS (D), DMFS (E), and OS (F) for variables by multivariate Cox analysis. *, p < 0.05; **, p < 0.01; ***, p < 0.001.
Figure 4
Figure 4
Combined status of CD8+ cell density and CTLA-4/CD86 expression with survival. (A) Kaplan-Meier curve for DMFS in low or high tCD8+ cell density groups according to CTLA-4 expression. (B,C) Kaplan-Meier curves for OS in low or high tCD8+ (B)/sCD8+ (C) cell density groups according to the CD86 expression. (D–F) Forest plots of PFS and DMFS for variables by multivariate Cox analysis in low tCD8+ (D,F)/sCD8+ (E) cell density groups. *, p < 0.05; **, p < 0.01; ***, p < 0.001.
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References

    1. Biller L.H., Schrag D. Diagnosis and Treatment of Metastatic Colorectal Cancer: A Review. JAMA. 2021;325:669–685. doi: 10.1001/jama.2021.0106. - DOI - PubMed
    1. Ganesh K., Stadler Z.K., Cercek A., Mendelsohn R.B., Shia J., Segal N.H., Diaz L.A., Jr. Immunotherapy in colorectal cancer: Rationale, challenges and potential. Nat. Rev. Gastroenterol. Hepatol. 2019;16:361–375. doi: 10.1038/s41575-019-0126-x. - DOI - PMC - PubMed
    1. Boland C.R., Thibodeau S.N., Hamilton S.R., Sidransky D., Eshleman J.R., Burt R.W., Meltzer S.J., Rodriguez-Bigas M.A., Fodde R., Ranzani G.N., et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res. 1998;58:5248–5257. - PubMed
    1. Huyghe N., Baldin P., Van den Eynde M. Immunotherapy with immune checkpoint inhibitors in colorectal cancer: What is the future beyond deficient mismatch-repair tumours? Gastroenterol. Rep. 2020;8:11–24. doi: 10.1093/gastro/goz061. - DOI - PMC - PubMed
    1. Petrelli F., Trevisan F., Cabiddu M., Sgroi G., Bruschieri L., Rausa E., Ghidini M., Turati L. Total Neoadjuvant Therapy in Rectal Cancer: A Systematic Review and Meta-analysis of Treatment Outcomes. Ann. Surg. 2020;271:440–448. doi: 10.1097/SLA.0000000000003471. - DOI - PubMed