VCU Institute of Molecular Medicine (VIMM) NEWS & VIEWS |
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The VIMM, established in 2008 by Paul B. Fisher, MPh, PhD, FNAI, the Founding Director, is comprised of outstanding scientists/clinicians from VCU School of Medicine and external affiliate members focusing on important medical-related research in cancer, neurodegeneration and infectious diseases. The purpose of this NEWS & VIEWS is to highlight the exciting research being performed by VIMM members.
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Breast cancer dormancy and immunotherapy
Research from Dr. Masoud H. Manjili and colleagues demonstrates that immune responses predominated by CD4+ and CD8+ T effector cell subsets could maintain tumor dormancy and prevent reawakening of breast cancer dormant cells.
- Dormant tumor cells are present at the site of primary breast cancer, and at distant sites in the lungs and liver very early in the course of early stage breast cancer.
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Dormant tumor cells are characterized as Ki67- and Ki67low fractions.
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Cancer therapies increase the proportion of Ki67- dormant tumor cells at the site of primary mammary carcinoma.
- Retention of distant tumor dormancy in the lungs or liver is associated with the predominance of infiltrating CD4+ and CD8+ Te (T effector) subsets.
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Dormant tumor cells isolated from the lungs can resume proliferation ex vivo.
- Dormant tumor cell lines are tumorigenic and establish distant tumor dormancy in the lungs and liver associated with the predominance of infiltrating Te and Tem (T effector/memory) subsets.
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Autologous tumor-sensitized T cells prevent re-growth of dormant tumor cells ex vivo.
- Presence of anti-tumor immune responses prior to tumor challenge results in complete protection of FVB mice from mammary carcinoma and distant tumor dormancy.
- The results suggest that personalized immunotherapies that target mutant neoantigens during tumor dormancy might prevent distant recurrence of the disease.
Progress in cancer therapies has led to improved survival of patients with early stage breast cancer. However, mortality remains high in patients with distant recurrence of the disease after initially successful treatment. Tumor recurrences have been attributed to the presence of dormant tumor cells in breast cancer patients. Therefore, timely detection, characterization and targeting of dormant tumor cells by an effective immunotherapy could prevent distant recurrence of the disease. New research from Dr. Masoud H. Manjili and colleagues published in Breast Cancer Research* demonstrated that immune responses predominated by CD4+ and CD8+ T effector cell subsets could maintain tumor dormancy and prevent reawakening of breast cancer dormant cells. The study also demonstrated the presence of dormant tumor cells at the site of primary breast cancer before and after neoadjuvant therapies, regardless of breast cancer type (Figure 1).
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Figure 1. Neoadjuvant therapies induce local tumor dormancy in patients with early stage breast cancer. Patients with HER2 positive breast cancer (Stages I-III) received neoadjuvant Pertuzumab, Trastuzumab, Docetaxel and Carboplatin, and those with TNBC received neoadjuvant Taxol, Carboplatin, Adriamycin and Cytoxan, followed by surgery. A) Tumor biopsies (before) and surgical excisions (after) neoadjuvant therapies of patients with triple negative breast cancer or HER2 positive breast cancer who partially responded (PR) to neoadjuvant therapies, were subjected to Ki67 staining. IHC analysis showing Ki67+ (brown) and Ki67- (blue), and percent Ki67- or Ki67+ in tumor biopsies (before, n=4) or surgical excisions (after, n=4) were analyzed using the Vectra® Polaris™ Automated Quantitative Pathology Imaging System and InForm software (PerkinElmer) (1x1 field, 20x resolution). B) Biopsy specimens of patients with early stage breast cancer who showed a complete response (CR) or no response (NR) to neoadjuvant therapies (5 patients per group) were analyzed for the expression of Ki67.
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Publications:
1) *Aqbi HF, Coleman C, Zarei M, Manjili SH, Graham L, Koblinski J, Guo C, Xie Y, Gurulu G, Bear HD, Wang XY, Manjili MH. Local and distant tumor dormancy during early stage breast cancer are associated with the predominance of infiltrating T effector subsets. Breast Cancer Res. 2020 Oct 28;22(1):116. PMCID: PMC7594332 DOI: 10.1186/s13058-020-01357-9
About the Investigators: Masoud H. Manjili, DVM, PhD, is Professor of Microbiology & Immunology, Member of the VCU Institute of Molecular Medicine (VIMM) and member of the VCU Massey Cancer Center (MCC), Virginia Commonwealth University, School of Medicine, Richmond, VA. Hussein Aqbi, PhD, is the first author of this research study, and along with Cara Coleman, Laura Graham, Jennifer Koblinski, Chunquing Guo, Georgi Guruli, Harry Bear, Michael Idowu and Xiang-Yang Wang from the VCU School of Medicine. Saeed Manjili is from the VCU School of Engineering, Melika Zarei is from Emory University School of Medicine, Mehran Habibi is from Johns Hopkins School of Medicine, and Yibin Xie is from Peking Union Medical College, Beijing, China.
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