Vascular endothelial growth factor inhibitors promote antitumor responses via tumor microenvironment immunosuppression in advanced colorectal cancer

Abstract

Purpose

This study aims to investigate changes in the tumor immune environment of patients who underwent therapy with a vascular endothelial growth factor (VEGF) inhibitor for advanced colorectal cancer.

Methods

Patients (n = 135) with T3 or T4 colorectal cancer were included in this retrospective study. They were classified as follows: patients who had not received preoperative treatment (UPFRONT group, n = 54), who had received FOLFOX as preoperative chemotherapy (FOLFOX group, n = 55), and who had undergone resection after combination FOLFOX and bevacizumab as unresectable colorectal cancer (B-MAB group, n = 26). The number of cytotoxic T lymphocytes (CTLs), FOXP3⁺ lymphocytes (including regulatory T cells (Tregs)), CD163⁺ monocytes (including M2-type tumor-associated macrophages (TAM-M2 type)), and programmed cell death 1 (PD-1)⁺ lymphocytes was evaluated immunohistochemically in the cancer cell area (CC) and stromal cell area (ST) of surgical specimens, and compared among the three groups.

Results

The CTL population did not differ among the three groups in both areas. In the B-MAB group, the numbers of PD-1⁺ cells in the ST, FOXP3⁺ lymphocytes in both areas, and CD163⁺monocytes in the ST was lower than that in the other two groups, and a correlation with the histological therapeutic effect was observed.

Conclusions

In advanced colorectal cancer, VEGF inhibitors may decrease the number of PD-1⁺ cells and inhibit the infiltration of FOXP3⁺ lymphocytes and CD163⁺monocytes into the tumor environment.

Keywords:

• Colorectal cancer
• vascular endothelial growth factor
• bevacizumab
• regulatory T cell
• M2-type tumor-associated macrophage
• programmed cell death 1

Acknowledgments

The authors thank Editage (www.editage.com) for English language editing.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by the JSPS KAKENHI under Grant JP21K08783.