Combination TIGIT/PD-1 blockade enhances the efficacy of neoantigen vaccines in a model of pancreatic cancer

Abstract

BackgroundCancer neoantigens are important targets of cancer immunotherapy and neoantigen vaccines are currently in development in pancreatic ductal adenocarcinoma (PDAC) and other cancer types. Immune regulatory mechanisms in pancreatic cancer may limit the efficacy of neoantigen vaccines. Targeting immune checkpoint signaling pathways in PDAC may improve the efficacy of neoantigen vaccines.MethodsWe used KPC4580P, an established model of PDAC, to test whether neoantigen vaccines can generate therapeutic efficacy against PDAC. We focused on two immunogenic neoantigens associated with genetic alterations in the CAR12 and CDK12 genes. We tested a neoantigen vaccine comprised of two 20-mer synthetic long peptides and poly IC, a Toll-like receptor (TLR) agonist. We investigated the ability of neoantigen vaccine alone, or in combination with PD-1 and TIGIT signaling blockade to impact tumor growth. We also assessed the impact of TIGIT signaling on T cell responses in human PDAC.ResultsNeoantigen vaccines induce neoantigen-specific T cell responses in tumor-bearing mice and slow KPC4580P tumor growth. However, KPC4580P tumors express high levels of PD-L1 and the TIGIT ligand, CD155. A subset of neoantigen-specific T cells in KPC4580P tumors are dysfunctional, and express high levels of TIGIT. PD-1 and TIGIT signaling blockade in vivo reverses T cell dysfunction and enhances neoantigen vaccine-induced T cell responses and tumor regression. In human translational studies, TIGIT signaling blockade in vitro enhances neoantigen-specific T cell function following vaccination.ConclusionsTaken together, preclinical and human translational studies support testing neoantigen vaccines in combination with therapies targeting the PD-1 and TIGIT signaling pathways in patients with PDAC.

The Role of Different Immunocompetent Cell Populations in the Pathogenesis of Head and Neck Cancer—Regulatory Mechanisms of Pro- and Anti-Cancer Activity and Their Impact on Immunotherapy

“…It inhibits effector T cell activation in vivo and NK cytotoxicity by binding to CD115 and CD112 molecules on dendritic cells (DCs) and macrophages (TAMs/MФ), but also to ligands on the tumour cell surface, thus facilitating the mechanisms of immune escape in the cancer immune cycle [ 405 , 406 , 407 , 408 ]. Importantly, TIGIT and programmed death-ligand 1 (PD-1) have been shown to be upregulated on tumour antigen-specific CD8 + T cells and CD8 + tumour infiltrating lymphocytes (TILs) in both HNSCC patients and mouse models; in addition, their level was correlated with other immune-checkpoint molecules, i.e., PD-1, TIM-3 and LAG-3 [ 409 , 410 , 411 ]. Therefore, a few clinical trials on TIGIT-blockade have recently been initiated, predominantly in combination with immune checkpoint co-blockade therapy against PD-L1 used in different human solid cancers [ 410 , 412 , 413 , 414 ].…”

“…Importantly, TIGIT and programmed death-ligand 1 (PD-1) have been shown to be upregulated on tumour antigen-specific CD8 + T cells and CD8 + tumour infiltrating lymphocytes (TILs) in both HNSCC patients and mouse models; in addition, their level was correlated with other immune-checkpoint molecules, i.e., PD-1, TIM-3 and LAG-3 [ 409 , 410 , 411 ]. Therefore, a few clinical trials on TIGIT-blockade have recently been initiated, predominantly in combination with immune checkpoint co-blockade therapy against PD-L1 used in different human solid cancers [ 410 , 412 , 413 , 414 ]. Blockade of these relevant immune checkpoint axes have been observed to enhance antitumour immune responses by activating T cell proliferation and function, cytokine production, degranulation of CTLs CD8 + T cells and TIL CD8 + T cells, as well as reducing the CD4 + CD25 + Foxp3 + T reg population and TGF-β1 secretion [ 407 , 409 , 415 , 416 ].…”

Developments and future prospects of personalized medicine in head and neck squamous cell carcinoma diagnoses and treatments

“…Thus, determining the HER2 status of the tumor can assist in locating patients who could get benefitted from HER2‐targeted therapies 34 . Genetic testing can assess the level of PD‐L1 expression in tumor cells, where vaccines, together with therapies focusing on the PD‐1 and TIGIT signaling pathways can help predict the potential response to immunotherapy 35 . Some HNSCC may have mutations in DNA repair genes like BRCA1 or BRCA2 36 .…”

“… 34 Genetic testing can assess the level of PD‐L1 expression in tumor cells, where vaccines, together with therapies focusing on the PD‐1 and TIGIT signaling pathways can help predict the potential response to immunotherapy. 35 Some HNSCC may have mutations in DNA repair genes like BRCA1 or BRCA2. 36 Identifying these mutations can have implications for treatment, as they may respond differently to certain therapies, such as PARP inhibitors.…”

Current and future immunotherapeutic approaches in pancreatic cancer treatment

“…In pancreatic cancer, the CD155/TIGIT axis plays a significant role in boosting and sustaining immune evasion [ 351 ]. Combining TIGIT and PD-1 blockade enhances the efficacy of vaccinations in a model of pancreatic cancer [ 352 ]. The reinvigoration of T lymphocytes specific to pancreatic tumor cells occurred as a result of the co-blockade of TIGIT/PD-1 and the stimulation of CD40 agonist [ 351 ].…”