Generating T Cell Responses in the Immunosuppressive Tumor Microenvironment

The ultimate promise of tumor immunotherapy is dependent on the generation of effective immunity against cancer, including CD4 and CD8 T cell responses. However, activating T cells in cancer types such as pancreatic ductal adenocarcinoma (PDAC) requires overcoming significant hurdles in the tumor microenvironment (TME). Local and systemic suppression of dendritic cell function restrains endogenous T cell immunity against PDAC, which is further exacerbated by tumor cell intrinsic recruitment of suppressive myeloid cells and macrophages to the tumor site. Agonistic anti-CD40 antibody, which mimics the endogenous CD40 ligand to license and mature dendritic cells and re-educate tumor-associated myeloid cells towards a Th1/M1 phenotype, may provide a mechanism by which to bypass the suppressive barriers in the PDAC TME. Using the KrasLSL-G12D/+,Trp53LSL-R172H/+,Pdx1-Cre (KPC) genetically engineered mouse model of pancreatic cancer, we show that combining standard-of-care chemotherapy with CD40 agonism promotes clonal T cell activation and expansion locally in the tumor site, resulting in regressions and cures of established tumors and further enhanced by the addition of dual immune checkpoint blockade (anti-PD-1 and anti-CTLA-4). These studies formed the preclinical rationale for trials investigating the use of agonistic CD40 therapy for patients with resectable or metastatic PDAC, and provided insight for immunological correlates of response in the clinical setting. More recently, we have reported on the negative impact of chemotherapy on the developing anti-tumor T cell response, emphasizing the need for additional investigations into the combination and sequencing of treatment modalities for enhanced outcomes in patients with PDAC. These studies reveal the potential potency of immune interventions in PDAC for patients with the greatest unmet clinical need.

Learning Objectives: 

1. Discuss the impact of CD40 stimulation on T cell activation in mouse models of pancreatic cancer.

2. Identify correlates of response after CD40 therapy in patients.

3. Consider the implications of chemotherapy on immunotherapy-induced T cell responses to tumors.