PCinBC · Plasma cell heterogeneity and dynamics in patient tumors
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-09-01 → 2022-05-30
- EU contribution
- €203,852
- Participants
- 1
- Scheme
- MSCA-IF
Lines connect the coordinator with its partners.
Results in brief
Plasma cell heterogeneity and dynamics in patient tumors
Breast cancer is the leading cancer among women worldwide and though there are various cancer therapies for breast cancer, many produce debilitating side effects and/or are ineffective for certain types of breast cancer. Targeting the immune system to treat tumors has revolutionized care for many cancers, but has not been as effective for breast cancer. Thus, there is an urgent need to expand breast cancer treatement options. Most current immunotherapies target T cells, but the tumor stroma is home to many immune cells, including B cell-derived antibody-producing Plasma cells, whose cancer-associated functions are less studied, but represent untapped reservoirs as therapeutic targets. Tumor-associated plasma cells infiltrate breast tumors and their presence often correlates with improved prognosis. A current bottleneck in the field is to uncover tumor-associated plasma cell dynamics within its spatial context. Single cell RNA-seq studies enable high resolution gene expression and BCR analysis; however, these studies require tissue dissociation, and thus, one cannot tell where plasma cells are in the tissue with respect to their environmental cues, which could provide important information as to their functions. Current spatial transcriptomic methods (developed by the host and Lundeberg labs) allow the study of gene expression (and by extension cells) in tissues. I therefore set out to study plasma cells within breast tumor using spatial transcriptomics and other methods. The goal with the project has been to understand several aspects of breast tumor-infiltrating plasma cell biology, including: their gene expression profiles, spatial relationships with other cells and tissue elements in the tumor (such as tumor cells), their lifespan, and other relevant information (for example their antigen receptor identities, the so-called B cell receptor, and what they bind to). Combined, this study helps to understand fundamental mechanisms of plasma cell activities within human breast tumors with the ultimate goal to provide new targets for anti-cancer therapy.
Data: CORDIS, © European Union
Project objective
During the last decade, the ability to treat cancer by targeting the immune system has revolutionized cancer care, but many patients still fail to respond to current immunotherapies, which mainly target T cells. Besides T cells, the tumor microenvironment is home to many other immune cells; however, we are still unable to accurately predict and target the functions of most tumor-infiltrating immune cells, particularly in human cancer. These cells and their tumor-associated functions represent an untapped reservoir of therapeutic targets. Plasma cells (PC), which are antibody-producing cells derived from B cells, frequently infiltrate solid tumors and their presence associates with positive prognosis across cancer types; yet, our knowledge of tumor-infiltrating PC remains limited. The goal of this project is two-fold: first, I aim to use single cell RNA-seq coupled with spatial transcriptomics (developed by the host lab) to define the heterogeneity and spatial distribution of PC (and their subsets) relative to other cells/histological features in patient breast tumors. PC receptor expression and survival factors will be mapped to generate a PC-tumor stroma 'interactome', which should facilitate defining potential vantage points for therapy. Second, I aim to define the cellular age of tumor-infiltrating PC, since knowing how cells are replaced in a tissue could be highly relevant to both uncover fundamental cell turnover mechanisms and to define new therapeutic avenues. The combination of skillsets between the applicant (tumor immunology) and the host lab (spatial transcriptomics and carbon dating, the latter which uniquely can be used to determine cellular lifespan in humans) presents a unique opportunity for the feasibility and knowledge exchange involved in performing this work. This study’s results could help clarify fundamental questions regarding the biology of tumor-infiltrating plasma cells and help uncover novel anticancer therapeutic targets.
Original text from CORDIS.
Participants
- KAROLINSKA INSTITUTET · STOCKHOLMCoordinatorSweden
Links
Data: CORDIS, © European Union