Abstract SP116: B-cells and follicular T cells regulate responses to immune checkpoint inhibitors in breast tumors and melanomas
Authors: Perou C 
Published: February 2021

Abstract
Triple Negative Breast Cancer (TNBC) makes up 10-15% of breast cancers, disproportionally affects African Americans, and if considered its own disease type, would rank as the #5 cause of cancer deaths in women in the USA each year. Among the most promising new therapeutic approaches for TNBC is immunotherapy using Immune Checkpoint Inhibitors (ICI). Many ICI trials for TNBC patients are underway with early results showing response rates to single agent ICI in the range of 10-20% in the metastatic setting. Thus, there is a good sign of efficacy, but the majority of TNBC patients still fail to respond, even despite the recent improvements made by combination regimens of ICI and chemotherapy. These findings illustrate a clear need for 1) improved biomarker(s) to identify the subset TNBC patients who will respond to current ICI-based regimens, and 2) improvements in ICI regimens that may include additional immune modulating therapeutics, and/or combinations with specific mechanistically chosen chemotherapeutics.
Improving response rates of breast cancer patients to immune checkpoint inhibitors requires an understanding of mechanism of action of ICI, and robust in vivo models to further evaluate mechanisms and to empirically test new regimens in the preclinical setting first. In our prior work, we identified and credentialed mouse models with genomic and transcriptomic similarities to human TNBC, and in a subtype aware manner. In completing these studies, we found that the majority of TNBC mouse models reflect those human tumors with low tumor mutation burden (TMB), and these models had low immune infiltrates. In our efforts to model human TNBCs with elevated tumor mutation burdens we “mutagenized” our low TMB models into the range of high TMB human TNBC. We found that these mouse models with high tumor mutation burden had increased tumor infiltrating lymphocytes and were now responsive to anti-PD1 and anti-CTLA4 immune checkpoint inhibitors. Specifically, we discovered that in ICI sensitive mouse models, CD4+ T follicular helper cells and B cells coactivate one another and both are necessary for the full effects of the anti-tumor response to immune checkpoint therapy. We further used additional genetically engineered mouse models to discover a requirement for active antibody production as being needed for an effective anti-tumor response to immune checkpoint therapy.
The direct and active involvement of B cells in response to ICI has recently been shown to also occur in melanoma patients. This suggests a broader role for B cells as being a key component of a coordinated anti-tumor immune response. In addition, we captured these mechanistic features within a small gene expression signature that we further demonstrated predicted response to ICI treatment in melanoma patients, to trastuzumab in HER2+ breast cancer patients, and to neoadjuvant chemotherapy in TNBC patients. To translate this knowledge to therapeutic advances, we are now using our mouse models to test if immunomodulators of B cells can improve T cell focused immunotherapies, some of which are showing promising results. In summary, the adaptive immune system is a critical component of response to multiple and diverse classes of drugs in breast cancer, including chemotherapy, HER2 targeting therapy, and ICI. Further studies aimed at boosting these responses could have a significant impact for many TNBC patients, and non-TNBC patients, as well.
Citation Format: C Perou. B-cells and follicular T cells regulate responses to immune checkpoint inhibitors in breast tumors and melanomas [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP116.