Sunday, May 5, 2024
5/5/2024
The clinical experience with anti-PD-1 immune checkpoint inhibition in ovarian cancer has been disappointing. The poor outcomes may at least in part be due to the highly immunosuppressive tumor microenvironment (TME) and the low tumor mutational burden in ovarian cancer, suggesting relatively limited immunogenicity and anti-tumor T cell responses. These barriers may be overcome by clinically relevant combinatorial treatments that (i) stimulate anti-tumor T cell immunity and (ii) alleviate immune suppression in the tumor microenvironment. Favorable clinical results from a recent trial of Th17-inducing dendritic cell (Th17-DC) vaccination in patients with stage III/IV ovarian cancer provided a strong foundation for Th17-DC vaccine- based combinatorial approaches to immunotherapy in ovarian cancer. Indeed, follow-up studies in a mouse model of ovarian cancer showed that Th17-DC vaccination could dramatically improve responses to anti-PD- 1 immune checkpoint inhibition. Several lines of evidence have pointed to a key role for B cell responses in the anti-tumor activity of Th17-DC vaccination. In this proposal, we will test the hypothesis that the efficacy of anti-PD-1/Th17-DC vaccination is dependent on host B cell responses in the following Specific Aims: Aim 1) Determine whether the efficacy of anti-PD-1/Th17-DC vaccination combinatorial immunotherapy is dependent on B cells We will evaluate the role of B cells in anti-PD-1/Th17-DC vaccine-induced antitumor immunity by in vivo depletion of B cells in the ID8 p53-/- and the ID8 p53-/- BRCA2-/- mouse models of ovarian cancer. Aim 2) Determine whether the efficacy of anti-PD-1/Th17-DC vaccination combinatorial immunotherapy is associated with the formation of tertiary lymphoid structures (TLS) We will correlate the prevalence and morphology of TLS in ID8 p53-/- and ID8 p53-/- BRCA2-/- ovarian tumors with therapeutic responses to anti-PD-1/Th17-DC vaccination. We will also identify TLS gene signatures associated with therapeutic responses. The potential synergy between Th17-DC vaccination and anti-PD-1 may have considerable impact for the future use of immune checkpoint inhibitors for treatment of ovarian cancer. The novel concept that the efficacy of Th17-DC vaccination (itself an innovation), either as monotherapy or combined with anti-PD-1 immune checkpoint inhibition, is ultimately dependent on B cell responses also has high impact for the field.
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