Boosting Immune Surveillance by Low-Dose PI3K Inhibitors for Early Breast Cancer Intervention
In an interview with Oncology Learning Network, Yuan Zhang, PhD, and Yi Xiao, PhD (pictured below: L-R), Molecular and Cellular Oncology Department, The University of Texas MD Anderson Cancer Center, discussed using low-dose PI3K inhibitors to boost immune surveillance and facilitate early intervention in patients with breast cancer. Dr Zhang is a postdoctoral fellow and mentee to Dihua Yu, MD, PhD, and Dr Xiao is an instructor in Dr Yu’s lab.
Dr Zhang: Thanks very much for this very great opportunity for us to share our recent work, "Boosting immune surveillance by low‑dose PI3K inhibitor facilitates early intervention of breast cancer." Dr Yi Xiao and Dr Jinyang Wang have made equal contribution to this work.
Previously, there are clinical trials that show tamoxifen and aromatase inhibitors successfully decrease the incidence of estrogen receptor (ER)‑positive breast cancer. However, no effective agents are available for the prevention of ER‑negative breast cancer, which have poor clinical outcomes when compared to ER‑positive breast cancer.
Therefore, there is an urgent need to develop strategies for prevention and early intervention for ER‑negative breast cancer.
There are several studies that show P13K Akt pathway is frequently upregulated in breast cancer. It is strongly associated with a poor prognosis in patients with HER2‑positive, ER‑negative breast cancer.
In our study, we first identified that P13K Akt pathway is significantly activated in premalignant ER‑negative breast lesions compared to normal tissue from breast cancer patients.
Then we want to know whether blocking P13K by both genetic knockdown or using low‑dose P13K inhibitor can inhibit ER‑negative tumor initiation. The answer is yes, blocking P13K indeed inhibit ER‑negative breast cancer initiation. The drug we use is GDC‑0941, which has been tested in clinical trial.
What about in vivo? We found that low‑dose GDC‑0941 can significantly delay tumor initiation and extended tumor‑free survival in transgenic mouse model of MMTV‑neu without showing any discernible adverse effects.
More interestingly, we found that low‑dose GDC treatment increases CD3, CD8, and Granzyme B‑positive T lymphocytes in mammary tissue compared with our vehicle treatment. This indicates an enhanced immune surveillance by low‑dose GDC treatment.
Cancer immune surveillance is critical in cancer prevention. It allows immune cells to recognize premalignant and malignant cells before they can cause harm. We wanted to examine whether or not low‑dose GDC treatment could modulate T cell recruitment to tumor cells.
Then we performed a T cell migration assay. We observed that increased CD3, CD8, CD4, and interferon‑gamma‑positive CD8 T cells migration toward tumor cells is significantly increased by GDC treatment.
Next, we investigated how inhibition of PI3K in tumor cells, with low‑dose GDC treatment, enhances T cell chemotaxis. We found that low‑dose GDC treatment increased the MRNA level of CC5 and CXCL10 in tumor cells both in vitro and in vivo. Further analysis showed that low‑dose of PI3K inhibitor enhances T cell recruitment in a CCL5/CXCL10‑dependent manner.
In summary, our study indicates that a low‑dose PI3K inhibitor may intervene early‑stage ER‑negative breast cancer development by enhancing immune surveillance via CC5 and CXCL10.
As we know that cancer vaccines have shown very good efficacy in secondary prevention of breast cancer, so it is anticipated that low‑dose PI3K inhibitor in combination with cancer vaccines may further improve the immunoprevention efficacy of the breast cancer.
The data in our study, along with other novel findings, can provide a scientific basis for developing new strategies for preventing of ER‑negative breast cancers in the future.
Dr Xiao: I want to emphasize one point. Previously, most studies using the PI3K inhibitor, they focus on targeting tumor cells. Our surprising findings revealed PI3K cannot influence only the tumor cell but can also have an impact on the tumor immunity.
Surprisingly, we found that it can enhance the T-cell recruitment. Previously, some reports suggesting high dosage of PI3K actually can inhibit T-cell proliferation. We actually inhibited tumor immunity, but we found a low dosage PI3K inhibitor treatment can increase the recruitment of T cell by upregulation of these critical T-cell chemo‑attractant.
In our study, we identified CCL5 and CXCL10 as the major chemokines that can recruit the T cell. That is the major interesting finding.
In our study, we only tested one PI3K inhibitor, GDC. This inhibitor is not clinically approved yet. However, we have 2 PI3K inhibitor that were just approved by the FDA. It is worth testing these 2 PI3K inhibitors for further prevention purpose, and I think this is the future of our work.