Cancer as a systemic disease
Description: Cancer is a systemic disease, meaning that it affects the whole body. Inherited and lifestyle factors impact tumor initiation and progression, and at the same time, primary tumors modify the entire body. Cancer incidence, including the risk of developing breast cancer, increases with age. Although cancer growth is driven by genetically abnormal (mutant) cells, such mutant cells can be detected even in normal tissues, such as in the non-cancerous breasts of healthy individuals. Thus, the presence of mutations is not sufficient to explain why tumors arise. However, increasing age is associated with progressive changes in the systemic and local tissue microenvironments including changes in immune-related functions. Immune responses become less effective with age, as demonstrated by older people being less likely to respond to vaccines. This age-related decline in immunity may contribute to the increase in tumorigenesis with age. The immune system attacks cancer cells with tumor-infiltrating leukocytes (white blood cells). Those cancer cells that survive this immune system attack are more aggressive and can become invasive and metastatic (spread throughout the body). We previously analyzed the immune environment of normal breast tissues, preinvasive breast tumors called ductal carcinoma in situ (DCIS), invasive ductal carcinomas (IDC), and distant metastatic lesions. We found the most significant differences between DCIS and IDC where the frequency of activated T cells (white blood cells that attack the tumor) was significantly lower in IDC compared to DCIS. We also found a significant decrease in TCR repertoire (reflecting how many different T cells are present) in IDC compared to DCIS. Distant metastatic lesions had a further decline in the frequency of activated T cells compared to IDC. These findings suggest a possible association between progressive decline in immune activity and tumor progression. Some of these changes are driven by host factors (e.g., age, obesity), while others by the primary tumor. More recently we analyzed the peripheral blood (blood circulating thru the body) TCR repertoire of breast cancer patients of different age diagnosed with DCIS or metastatic disease to identify possible age and tumor progression stage-related differences. We found that TCR repertoire declined with age and among young patients those diagnosed with metastatic breast cancer had less diverse TCR repertoire. Based on these data we hypothesize that (1) pre-existing immunity, reflecting prior immune responses based on TCR repertoire of peripheral blood is associated with risk of progression to metastatic disease, (2) TCR repertoire of peripheral blood and within the tumor correlate with each other, (3) TCR repertoire diversity defines tumor evolutionary paths via immune selection and this may accelerate progression, and (4) host factors (e.g., age and obesity) influence tumor evolution via modulating the immune environments. The goal of this proposal is to test these hypotheses by analyzing human tissue samples and using a rat model of breast cancer.
Funder: American Cancer Society
Amount: $400,000
Funding type: award
Start date: 2023-01-01
End date: 2027-12-31
Investigators: Kornelia Polyak, Jean Kane, Emy Chen, Leslie Colon, Benjamin Ebert, Amy Ehrenzweig
Institution: Dana-Farber Cancer Institute
Funded outputs count: 1
Funder award ID: RP-22-184-01-MM
OpenAlex ID: G8369709552