First, to better understand plasma cell phenotypes within their tissue microenvironment in breast cancer, we have collected and generated large datasets from a set of 6 individual untreated breast cancer patients, diagnosed with either Her2 positive tumors or Triple Negative breast tumors. We selected these patients since they are more likely to have high immune cell infiltration in their tumors and in the case of TNBC, lack targeted treatment options. For these patients, we have collected samples from several different tumor regions and generated datasets that include all immune cells (including plasma cells), tumor cells, spatial transcriptomics, exome sequencing, protein content, and antigen receptor information. We have found that: the amount of plasma cells (and the related B cells) varies greatly between patients, that the number of plasma cells per tumor is likely underestimated using single cell transcriptomics methods, that breast tumor tissue contains high antibody content, and that tumor-associated antibodies most commonly are of the IGG, IGA, or IGM isotype. In developing a map of plasma cell interactions with tumor cells directly, we have also set out to develop the tumor clonal evolution within the same samples. To do this, we have profiled the tumor cells in depth to understand their lineage relationships and how they relate to each other. Then we have used the spatial transcriptomics data to map these tumor cell clones within the tissue. This work will help to understand the interactions between distinct plasma cells and the tumors. This work is on-going and we are working towards generating a draft for publishing these results.
Second, in parallel, I have contributed to understanding plasma cells within breast tumors using already collected patient material from HER2 positive breast tumors (Andersson et al. Nature Communications 2021). Here, we found that: plasma cells located away from tumor cells and B cells, but instead located proximal to other immune cell types, including macrophage subsets. In this published article, we also developed a tool to predict the location of tertiary lymphoid structures in tissues using spatial transcriptomics data. These structures are important activation centers for immune cells, including B and plasma cells, within tumors (and other inflamed tissues). Together, these findings can form the basis for future functional studies into the mechanisms and roles of these interactions. These results have been published and the corresponding datasets are available to the public.
Third, to better understand plasma cell lineage relationships (i.e. using the B cell receptor as an endogenous cellular barcode to track cells) and antigen receptor information within breast tumors, we are using these generated datasets to extend the spatial transcriptomics method to enable measuring these aspects in tumor tissue sections. This method is expected to be applicable to understanding plasma cell biology beyond breast cancer, including in the context of infection, vaccine responses, and autoimmunity.
