Combining toll-like receptor agonists with immune checkpoint blockade affects antitumor vaccine efficacy
Donghwan Jeon1, Ethan Hill2, Jena E Moseman1
1Cancer Biology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Background:
T cell checkpoint receptors are expressed when T cells are activated, and modulation of the expression or signaling of these receptors can alter the function of T cells and their antitumor efficacy. We previously found that T cells activated with cognate antigen had increases in the expression of PD-1, and this was attenuated in the presence of multiple toll-like receptor (TLR) agonists, notably TLR3 plus TLR9. In the current report, we sought to investigate whether combining TLR agonists with immune checkpoint blockade can further augment vaccine-mediated T cell antitumor immunity in murine tumor models.
Methods:
TLR agonists (TLR3 plus TLR9) and immune checkpoint inhibitors (antibodies targeting PD-1, CTLA-4, LAG-3, TIM-3 or VISTA) were combined and delivered with vaccines or vaccine-activated CD8+T cells to E.G7-OVA or MyC-CaP tumor-bearing mice. Tumors were assessed for growth and then collected and analyzed by flow cytometry.
Results:
Immunization of E.G7-OVA tumor-bearing mice with SIINFEKL peptide vaccine, coadministered with TLR agonists and αCTLA-4, demonstrated greater antitumor efficacy than immunization with TLR agonists or αCTLA-4 alone. Conversely, the antitumor efficacy was abrogated when vaccine and TLR agonists were combined with αPD-1. TLR agonists suppressed PD-1 expression on regulatory T cells (Tregs) and activated this population. Depletion of Tregs in tumor-bearing mice led to greater antitumor efficacy of this combination therapy, even in the presence of αPD-1. Combining vaccination with TLR agonists and αCTLA-4 or αLAG-3 showed greater antitumor than with combinations with αTIM-3 or αVISTA.
Conclusion:
The combination of TLR agonists and αCTLA-4 or αLAG-3 can further improve the efficacy of a cancer vaccine, an effect not observed using αPD-1 due to activation of Tregs when αPD-1 was combined with TLR3 and TLR9 agonists. These data suggest that optimal combinations of TLR agonists and immune checkpoint blockade may improve the efficacy of human anticancer vaccines.
Insights
Combining toll-like receptor (TLR) agonists with certain immune checkpoint inhibitors, like anti-CTLA-4, enhances cancer vaccine efficacy. However, combining TLR agonists with anti-PD-1 abrogated efficacy due to regulatory T cell activation.
Area of Science:
- Immunology
- Cancer Research
- Vaccinology
Background:
- T cell checkpoint receptors regulate T cell function and antitumor efficacy.
- Toll-like receptor (TLR) agonists can modulate T cell activation and PD-1 expression.
- Previous findings showed TLR agonists attenuated PD-1 expression on T cells activated by cognate antigen.
Purpose of the Study:
- To investigate if combining TLR agonists with immune checkpoint blockade can augment vaccine-mediated T cell antitumor immunity.
- To evaluate the efficacy of combined TLR agonists and various immune checkpoint inhibitors in murine tumor models.
Main Methods:
- TLR agonists (TLR3 plus TLR9) and immune checkpoint inhibitors (anti-PD-1, anti-CTLA-4, anti-LAG-3, anti-TIM-3, anti-VISTA) were combined with vaccines or vaccine-activated CD8+ T cells.
- Treatments were administered to E.G7-OVA or MyC-CaP tumor-bearing mice.
- Tumor growth was assessed, and tumors were analyzed by flow cytometry.
Main Results:
- Combination of SIINFEKL peptide vaccine, TLR agonists, and anti-CTLA-4 showed superior antitumor efficacy compared to individual treatments.
- Combining vaccine and TLR agonists with anti-PD-1 abrogated antitumor efficacy, linked to TLR agonist-induced PD-1 suppression and regulatory T cell (Treg) activation.
- Depletion of Tregs enhanced the efficacy of the combination therapy, even with anti-PD-1, suggesting Tregs mediate the abrogation.
- Combinations with anti-CTLA-4 or anti-LAG-3 demonstrated greater antitumor effects than those with anti-TIM-3 or anti-VISTA.
Conclusions:
- Combining TLR agonists with anti-CTLA-4 or anti-LAG-3 can significantly improve cancer vaccine efficacy.
- The use of anti-PD-1 in combination with TLR agonists was ineffective due to Treg activation.
- Optimal combinations of TLR agonists and immune checkpoint blockade hold promise for enhancing human anticancer vaccines.
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