CCL5-deficiency enhances intratumoral infiltration of CD8+ T cells in colorectal cancer

Shengbo Zhang,Wei-Qiang Gao,Yanjie Xu,Chao Wang,Yan Zhang,Ming Zhong

doi:10.1038/s41419-018-0796-2

Abstract

Colorectal cancer (CRC) is the third most common solid tumor in the world and shows resistance to several immunotherapies, particularly immune checkpoint blockade which has therapeutic effects on many other types of cancer. Cytotoxic CD8+ T cell has been considered as one of the main populations of effector immune cells in antitumor immunity; however, the absence of CD8+ T cells in the central tumor area has become a major obstacle for solid tumor immunotherapy, particularly for CRC. Thus, novel therapeutic strategies that could promote CD8+ T cells to accumulate in the central tumor area are urgently needed. Here, we demonstrated that CCL5-deficiency delayed tumor growth and metastasis via facilitating CD8+ T cells to accumulate into tumor site in CRC mouse models. Furthermore, CCL5-deficiency could upregulate PD-1 and PD-L1 expression and reduce the resistance to anti-PD-1 antibody therapy in CRC mouse model. Mechanically, the results of RNA-sequencing, in vitro coculture system and hypoxia measurements demonstrated that knockdown of CCL5 could result in the metabolic disorders in CD11bhiF4/80low TAMs and suppress the expression of S100a9 to promote the migration of CD8+ T cells in the tumor microenvironment. These findings were verified by the data of clinical samples from CRC patients, suggesting that CCL5 may provide a potential therapeutic target for the combined PD-1-immunotherapy of CRC.

Highlights

Colorectal cancer (CRC) is the third most common cancer and the estimated number of new CRC cases was 71,420 in men and 64,010 in women in the USA in 20171,2
We demonstrated that CC chemokine ligand 5 (CCL5)-deficiency inhibited tumor growth and metastasis of CRC by increasing the infiltration of CD8+ T cells into central tumor area
To provide further evidence on the conclusion that CCL5 suppresses CD8+ T cells accumulation via secreting S100a8/a9, we examined the correlation between the expression level of CCL5 and S100a8/a9 and the number of CD8+ T cells infiltrated in the tumor of CRC patients

Summary

Introduction

Colorectal cancer (CRC) is the third most common cancer and the estimated number of new CRC cases was 71,420 in men and 64,010 in women in the USA in 20171,2. The development of immunotherapies, including immune checkpoint inhibitors, chimeric antigen receptor (CAR)expressing T cells and tumor vaccines, have made great progress in cancer treatment generally via liberating the killing power of T cells[3,4]. Cancer immunotherapies have shown considerable clinical benefits in various cancers;. The presence of activated CD8+ T cells in tumor sites has been proved to be a significant positive prognostic marker for clinical response to immune checkpoints inhibitors in CRC7–11. Clinical response to anti-PD-1 Ab was found to occur almost exclusively in patients with pre-existing T cells infiltration[5,12,13]. New methods to enhance intratumoral infiltration of CD8+ T cells are an urgent need for CRC patients to benefit from the immunotherapies

Methods

Results

Conclusion