Group 2 Innate Lymphoid Cell Regulation of Pancreatic Cancer Immunity

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY/ABSTRACT Immunotherapies that boost anti-tumor T cells are landmark breakthroughs in oncology. Yet, current immunotherapies directly activate T cells and are therefore ineffective in ~80% of tumors with few T cells (“cold” tumors). Thus, a primary challenge in oncology is to develop effective immunotherapies for cold tumors. Pancreatic ductal adenocarcinoma (PDAC) is a prime example – ~91% of tumors have few T cells, and thus PDAC rarely responds to current immunotherapies (<2% response rate). Yet, immunotherapy is the most promising option in PDAC, as all other therapies have failed, and only the rare (9%) patients with immunogenic “hot” tumors (high density of intratumoral T cells) survive long-term. Thus, new immunotherapies are urgently needed for PDAC, and the principles can be applied to other cold tumors. To discover new targets that active immunity in PDAC, we contrasted immune cells in hot tumors from rare long- term PDAC survivors to those in more typical cold tumors from short-term survivors. Unexpectedly, we found that hot tumors have ~3-fold higher densities of group 2 innate lymphoid cells (ILC2s) (Moral et al., Nature, 2020). ILC2s are lymphocytes that amplify CD4+ Th2 cells in infection but paradoxically can activate CD8+ T cells in tumors. Using mouse models, we found that ILC2s recruit CD103+ dendritic cells to activate CD8+ T cells and suppress primary PDACs. Through further studies, we have now found that unlike currently presumed, ILC2s can also migrate to suppress metastatic PDAC tumors, express lymphotoxin (LT), a protein that induces tertiary lymphoid structures in tumors, and express the immune checkpoint PD-1 that regulates their anti-tumor function. As we are the first group to report that ILC2s can activate immunity in PDAC, the mechanisms by which ILC2s suppress PDACs, which can thus inform rational strategies to harness them in immunotherapies, are unknown. Thus, we now propose to study how ILC2s migrate to tumors, activate CD8+ T cells, and are functionally regulated. Through integrated, multi-disciplinary study of ILC2 phenotype and function in human PDAC patients, patient-derived organoids, and functional studies in mouse models, we will: 1) define the cytokines that mobilize anti-tumor ILC2s; 2) investigate how anti-tumor ILC2s utilize LT to activate CD8+ T cells; and 3) demonstrate how PD-1 blockade enhances anti-tumor ILC2 function. To ensure a cross-disciplinary approach, we will use an experienced team of investigators with complementary skills in PDAC biology, ILC2 immunology, immunotherapy, organoid models, and computational oncology. We expect our proposal will lay the scientific framework to understand ILC2 cancer biology and guide efforts to harness ILC2s in new immunotherapies.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE As current immunotherapies boost T cells to kill cancers, they are ineffective in ~80% of tumors that contain too few T cells (“cold” tumors). We have identified a new immunotherapy to activate a new immune cell called group 2 innate lymphoid cells (ILC2s), which increase T cells to control pancreatic cancer, a deadly cold tumor. We now propose to study how ILC2s increase T cells in pancreatic cancer, so that we may identify better ways to activate ILC2s in immunotherapies.