|The following article features coverage from the 2020 San Antonio Breast Cancer Symposium. Click here to read more of Cancer Therapy Advisor‘s conference coverage.|
Preclinical evidence suggests that stimulating the immune system with agents may bypass MYC — an oncogene that suppresses T cells — and improve the efficacy of immunotherapy in triple-negative breast cancer (TNBC).
The study findings were presented at the 2020 Virtual San Antonio Breast Cancer Symposium (SABCS).
Study researchers conducted a series of experiments to characterize MYC in TNBC and ways to bypass it, with the goal of making immune checkpoint inhibitors more effective in TNBC.
Using a data set of patients with TNBC from The Cancer Genome Atlas, study researchers found that a higher MYC gene signature was associated with less tumor-infiltrating leukocyte genes, which indicates that tumors with more MYC have less immune-cell infiltration.
In a mouse model for breast cancer in which MYC expression could be controlled, study researchers found that although tumor immune cells expressed programmed cell death ligand-1 (PD-L1), tumors that expressed MYC did not respond to anti–PD-L1 therapy. Further, when MYC was turned off, mice that received anti–PD-L1 therapy had tumor shrinkage, but eventually the tumors grew back.
B2M, a component of the major histocompatibility (MHC) class 1, was inversely associated with the MYC gene signature, and when MYC was turned off in mice, more MHC appeared on the surface of cells.
“Because we cannot directly remove or inhibit MYC in patients, we asked, what strategies might we use to overcome MYC suppression of MHC class 1 on tumors?” said study presenter Joyce Lee, PhD, postdoctoral fellow, University of California, San Francisco.
The researchers turned to 2 immunostimulatory agents: CpG and anti-OX40.
When mice were injected with CpG and anti-OX40, 33% of the animals had tumor regression. When anti–PD-L1 therapy was added to the combination, 75% of mice had tumor regression. Further, when a tumor was transplanted in a different mammary gland, the mice who received the triple-combination therapy continued to live disease free.
Lastly, a retrospective analysis of a small group of patients with hormone receptor-negative, HER2-negative breast cancer who received pembrolizumab on the I-SPY2 trial revealed that patients with a positive MYC gene signature tended to have disease recurrence.
“Therefore, we think additional agents to stimulate the immune system and increase MHC class 1 expression could help improve anti–PD-1 therapies for TNBC patients,” Dr Lee concluded.
Read more of Cancer Therapy Advisor‘s coverage of the 2020 SABCS meeting by visiting the conference page.
Lee JV, Housley F, Yau C, et al. The MYC oncogene suppresses tumor immune infiltration and function which is reversible with combinatorial immunotherapies. Presented at: 2020 Virtual San Antonio Breast Cancer Symposium; December 8-11, 2020. Abstract GS1-08.