Multiomics Empowers Predictive Pancreatic Cancer Immunotherapy

Abstract

Advances in cancer immunotherapy, particularly immune checkpoint inhibitors, have dramatically improved the prognosis for patients with metastatic melanoma and other previously incurable cancers. However, patients with pancreatic ductal adenocarcinoma (PDAC) generally do not respond to these therapies. PDAC is exceptionally difficult to treat because of its often late stage at diagnosis, modest mutation burden, and notoriously complex and immunosuppressive tumor microenvironment. Simultaneously interrogating features of cancer, immune, and other cellular components of the PDAC tumor microenvironment is therefore crucial for identifying biomarkers of immunotherapeutic resistance and response. Notably, single-cell and multiomics technologies, along with the analytical tools for interpreting corresponding data, are facilitating discoveries of the systems-level cellular and molecular interactions contributing to the overall resistance of PDAC to immunotherapy. Thus, in this review, we will explore how multiomics and single-cell analyses provide the unprecedented opportunity to identify biomarkers of resistance and response to successfully sensitize PDAC to immunotherapy.

Figure 1:. Multiomic profiling of T cells in PDAC can identify mechanisms of immunotherapy resistance.

a. T cells in PDAC are generally sparse, exhausted, and have few neo-antigenic targets for effective tumor cell killing. b. Single-cell technologies can simultaneously reveal T cell phenotypes, clonal dynamics over time and across tissues, and antigen specificity.

Figure 2:. Profiling cellular components of the PDAC TME through multiomics.

a. Specific cells within the PDAC TME, including myeloid derived suppressor cells (MDSCs), tumor-associated macrophages, and cancer-associated fibroblasts (CAFS) contribute to immunosuppression via signaling molecules and immune checkpoint expression. b. Single cell technologies can reveal novel cellular phenotypes and interactions responsible for immunotherapeutic response and resistance in PDAC. c. Spatial technologies are rapidly advancing and have the potential to enhance our understanding of molecular interactions responsible for therapeutic outcomes in patients with PDAC. More examples of relevant technologies can be found in Table 1.