PD-1 or PD-L1 Blockade Restores Antitumor Efficacy Following SSX2 Epitope-Modified DNA Vaccine Immunization
Brian T Rekoske1, Heath A Smith2, Brian M Olson3
1Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin.
Abstract:
DNA vaccines have demonstrated antitumor efficacy in multiple preclinical models, but low immunogenicity has been observed in several human clinical trials. This has led to many approaches seeking to improve the immunogenicity of DNA vaccines. We previously reported that a DNA vaccine encoding the cancer-testis antigen SSX2, modified to encode altered epitopes with increased MHC class I affinity, elicited a greater frequency of cytolytic, multifunctional CD8(+) T cells in non-tumor-bearing mice. We sought to test whether this optimized vaccine resulted in increased antitumor activity in mice bearing an HLA-A2-expressing tumor engineered to express SSX2. We found that immunization of tumor-bearing mice with the optimized vaccine elicited a surprisingly inferior antitumor effect relative to the native vaccine. Both native and optimized vaccines led to increased expression of PD-L1 on tumor cells, but antigen-specific CD8(+) T cells from mice immunized with the optimized construct expressed higher PD-1. Splenocytes from immunized animals induced PD-L1 expression on tumor cells in vitro. Antitumor activity of the optimized vaccine could be increased when combined with antibodies blocking PD-1 or PD-L1, or by targeting a tumor line not expressing PD-L1. These findings suggest that vaccines aimed at eliciting effector CD8(+) T cells, and DNA vaccines in particular, might best be combined with PD-1 pathway inhibitors in clinical trials. This strategy may be particularly advantageous for vaccines targeting prostate cancer, a disease for which antitumor vaccines have demonstrated clinical benefit and yet PD-1 pathway inhibitors alone have shown little efficacy to date.
Insights
Optimized DNA vaccines targeting cancer-testis antigen SSX2 showed reduced antitumor effects by increasing PD-1/PD-L1 expression. Combining these vaccines with PD-1 pathway inhibitors may improve cancer immunotherapy, especially for prostate cancer.
Area of Science:
- Immunology
- Oncology
- Vaccinology
Background:
- DNA vaccines show preclinical antitumor promise but face low immunogenicity in human trials.
- Optimizing DNA vaccines for enhanced CD8(+) T cell response is crucial for improving cancer immunotherapy.
- Cancer-testis antigens like SSX2 are targets for novel cancer vaccines.
Purpose of the Study:
- To evaluate the antitumor activity of an optimized SSX2 DNA vaccine in a preclinical tumor model.
- To investigate the immunological mechanisms underlying the vaccine's efficacy and potential limitations.
- To determine if combining the optimized vaccine with immune checkpoint inhibitors enhances antitumor effects.
Main Methods:
- Developed an optimized DNA vaccine encoding SSX2 with enhanced MHC class I affinity.
- Administered native and optimized vaccines to tumor-bearing mice with SSX2-expressing tumors.
- Assessed tumor growth, T cell responses (CD8+), and immune checkpoint molecule expression (PD-1/PD-L1).
- Evaluated combination therapies with PD-1/PD-L1 blocking antibodies.
Main Results:
- The optimized vaccine showed inferior antitumor activity compared to the native vaccine in tumor-bearing mice.
- Both vaccines increased PD-L1 expression on tumor cells; optimized vaccine increased PD-1 on CD8+ T cells.
- In vitro studies confirmed splenocytes from immunized mice induced PD-L1 on tumor cells.
- Combination therapy with PD-1/PD-L1 blockade or targeting PD-L1-negative tumors improved antitumor effects.
Conclusions:
- Optimized DNA vaccines targeting SSX2 may inadvertently enhance immune suppression via the PD-1/PD-L1 pathway.
- Combining DNA vaccines with PD-1 pathway inhibitors could be a viable strategy for cancer immunotherapy.
- This approach may be particularly relevant for prostate cancer, where current immunotherapies have limited efficacy.
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