Vaccine Increases the Diversity and Activation of Intratumoral T Cells in the Context of Combination Immunotherapy.
Lucas A HornKristen FousekDuane H HamiltonJames W HodgeJohn A ZebalaDean Y MaedaJeffrey SchlomClaudia PalenaPublished in: Cancers (2021)
Resistance to immune checkpoint blockade therapy has spurred the development of novel combinations of drugs tailored to specific cancer types, including non-inflamed tumors with low T-cell infiltration. Cancer vaccines can potentially be utilized as part of these combination immunotherapies to enhance antitumor efficacy through the expansion of tumor-reactive T cells. Utilizing murine models of colon and mammary carcinoma, here we investigated the effect of adding a recombinant adenovirus-based vaccine targeting tumor-associated antigens with an IL-15 super agonist adjuvant to a multimodal regimen consisting of a bifunctional anti-PD-L1/TGF-βRII agent along with a CXCR1/2 inhibitor. We demonstrate that the addition of vaccine induced a greater tumor infiltration with T cells highly positive for markers of proliferation and cytotoxicity. In addition to this enhancement of cytotoxic T cells, combination therapy showed a restructured tumor microenvironment with reduced Tregs and CD11b+Ly6G+ myeloid cells. Tumor-infiltrating immune cells exhibited an upregulation of gene signatures characteristic of a Th1 response and presented with a more diverse T-cell receptor (TCR) repertoire. These results provide the rationale for the addition of vaccine-to-immune checkpoint blockade-based therapies being tested in the clinic.
Keyphrases
- combination therapy
- papillary thyroid
- dendritic cells
- squamous cell
- signaling pathway
- primary care
- bone marrow
- early stage
- cell proliferation
- gene expression
- dna methylation
- transforming growth factor
- young adults
- copy number
- regulatory t cells
- high glucose
- cell migration
- smoking cessation
- endothelial cells
- cell death
- highly efficient
- mesenchymal stem cells
- metal organic framework
- high throughput sequencing