Neutrophil extracellular traps blockade in combination with PD-1 inhibition in treatment of colorectal cancer metastasis.

Journal of Clinical Oncology (2020)

Neutrophil extracellular traps blockade in combination with PD-1 inhibition in treatment of colorectal cancer metastasis.

Publication Type  Journal article
 Authors Amblessed Onuma

Jiayi He

Yujia Xia

Hongji Zhang

Dmitry Genkin

George Tetz

 Abstract Background: Immune checkpoint inhibitors (ICIs) are currently approved for microsatellite instability-high metastatic colorectal cancer (mCRC) however reported objective response rate to monotherapy range between 28-52%. Neutrophil Extracellular Traps (NETs), an extracellular network of DNA and proteins expelled by neutrophils into the tumor microenvironment, promote CRC metastasis by inducing potent immunosuppressive effects. We hypothesize that targeting this network may improve response rates to immune checkpoint therapy. The purpose of our study is to investigate the effect of combination DNase I treatment, a NET depleting agent, and PD-1 blockade in mCRC progression.

Methods: Subcutaneous MC38 (MSI-H adenocarcinoma of the colon) tumors were established in 6-week-old mice. Treatment was initiated six days after tumor inoculation with daily intraperitoneal (i.p) injections of DNase I followed by i.p anti-PD-1 treatment administered every 3 days. Animals were divided into treatment groups: control, DNase alone, anti-PD-1 alone and combination of DNase I with anti-PD-1 (n = 6 mice/ group).

Results: Tumors were successfully established after 6 days of inoculation. These tumors expressed high neutrophil infiltration and NETs. To determine the effects of combination therapy on tumor progression, we measured tumor volume and time to progression (TTP). We found that mice treated with combination DNase I and anti-PD-1 had significantly lower mean tumor volume compared to anti-PD-1 alone (1372.68mm3 vs 2193.20 mm3, p-value = 0.043). TTP was higher in the combination group compared to anti-PD-1 treatment alone (median time to progression 22 vs 17 days, p-value = 0.004). Next we sought to determine the mechanism behind this effect by investigating if NETs blockade modulated the tumor microenvironment. We found that treatment with DNase I decreased exhaustion of CD8+ T-cells in the tumor compared to no treatment.

Conclusions: Targeting NETs in combination with immune checkpoint inhibition may be an option to improve response rate to immune checkpoint inhibitors through decreasing exhausted CD8+ T-cells.

Year of
 Journal Journal of Clinical Oncology
 DOI 10.1200/JCO.2020.38.15_suppl.e16002