Abstract
(1) Background: Targeting inhibitory immune checkpoint molecules has highlighted the need to find approaches enabling the activation of immune responses against cancer. Therapeutic vaccination, which induces specific immune responses against tumor antigens (Ags), is an attractive option. (2) Methods: Utilizing a K-RasG12Dp53null murine lung cancer model we determined tumor burden, tumor-infiltrating T cell (TIL) cytolysis, immunohistochemistry, flow cytometry, and CD4 and CD8 depletion to evaluate the efficacy of PD-1 blockade combined with CCL21-DC tumor lysate vaccine. (3) Results: Anti-PD-1 plus CCL21-DC tumor lysate vaccine administered to mice bearing established tumors (150 mm3) increased expression of perforin and granzyme B in the tumor microenvironment (TME), increased tumor-infiltrating T cell (TIL) activity, and caused 80% tumor eradication. Mice with treatment-induced tumor eradication developed immunological memory, enabling tumor rejection upon challenge and cancer-recurrence-free survival. The depletion of CD4 or CD8 abrogated the antitumor activity of combined therapy. PD-1 blockade or CCL21-DC tumor lysate vaccine monotherapy reduced tumor burden without tumor eradication. (4) Conclusion: Immune checkpoint blockade promotes the activity of the therapeutic cancer vaccine. PD-1 blockade plus CCL21-DC tumor lysate vaccine therapy could benefit lung cancer patients.
Highlights
Lung cancer is the leading cause of cancer death among men and women in the United States and worldwide; more than 1.9 million people died from lung cancer in 2017 [1]
The anti-PD-1, CCL21-dendritic cells (DCs) tumor lysate vaccine, and anti-PD-1 plus CCL21-DC tumor lysate vaccine treatments resulted in 3, 3, and 19-fold weight changes of tumors at the end of therapy in comparison to control, respectively
In comparison to the monotherapy that reduced tumor burden without causing tumor eradication, treatment groups receiving CCL21-DC tumor lysate vaccine plus anti-PD-1 led to 80%
Summary
Lung cancer is the leading cause of cancer death among men and women in the United States and worldwide; more than 1.9 million people died from lung cancer in 2017 [1]. Long-term survival after resection for non-small-cell lung cancer (NSCLC) is about 50% with advances in radiation therapy, chemotherapy, and molecular targeted therapies [1]. Therapeutic cancer vaccines, which induce a specific immune response against tumor antigens (Ags) are an attractive option. This strategy has shown low clinical efficacy when combined with other treatment modalities [3]. As recent advances that led to the approval of ipilimumab, PD-1 and PD-L1 inhibitors have revolutionized cancer immunotherapy and become well established as highly effective treatment options for managing patient outcomes [4,5]. Therapeutic cancer vaccines can induce a specific T cell immune response against tumor Ags, the PD-1/PDL-1
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