Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression
Joseph S. Dolina, … , Bjoern Peters, Stephen P. Schoenberger
Joseph S. Dolina, … , Bjoern Peters, Stephen P. Schoenberger
Published September 1, 2023
Citation Information: J Clin Invest. 2023;133(17):e164258. https://doi.org/10.1172/JCI164258.
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Research Article Oncology

Linked CD4+/CD8+ T cell neoantigen vaccination overcomes immune checkpoint blockade resistance and enables tumor regression

Abstract

Therapeutic benefit to immune checkpoint blockade (ICB) is currently limited to the subset of cancers thought to possess a sufficient tumor mutational burden (TMB) to allow for the spontaneous recognition of neoantigens (NeoAg) by autologous T cells. We explored whether the response to ICB of an aggressive low-TMB squamous cell tumor could be improved through combination immunotherapy using functionally defined NeoAg as targets for endogenous CD4+ and CD8+ T cells. We found that, whereas vaccination with CD4+ or CD8+ NeoAg alone did not offer prophylactic or therapeutic immunity, vaccines containing NeoAg recognized by both subsets overcame ICB resistance and led to the eradication of large established tumors that contained a subset of PD-L1+ tumor-initiating cancer stem cells (tCSC), provided the relevant epitopes were physically linked. Therapeutic CD4+/CD8+ T cell NeoAg vaccination produced a modified tumor microenvironment (TME) with increased numbers of NeoAg-specific CD8+ T cells existing in progenitor and intermediate exhausted states enabled by combination ICB-mediated intermolecular epitope spreading. We believe that the concepts explored herein should be exploited for the development of more potent personalized cancer vaccines that can expand the range of tumors treatable with ICB.

Authors

Joseph S. Dolina, Joey Lee, Spencer E. Brightman, Sara McArdle, Samantha M. Hall, Rukman R. Thota, Karla S. Zavala, Manasa Lanka, Ashmitaa Logandha Ramamoorthy Premlal, Jason A. Greenbaum, Ezra E. W. Cohen, Bjoern Peters, Stephen P. Schoenberger

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Figure 6

Anti-PD-1 checkpoint blockade additively increases Cltc

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Anti-PD-1 checkpoint blockade additively increases Cltc Δ15-specific me...
Δ15-specific memory frequency and promotes dominant intermolecular epitope spreading. C3H/HeJ mice vaccinated with 50 μg polyI:C alone or in combination with prime/boost regimens of a 5 × 5 μg mixture containing solubilized Mut_44, Mut_48, Mut_61, Mut_65, and Mut_67 long peptides. All groups of mice were challenged with 5 × 105 live SCC VII-Luc/GFP cells 31 days after primary vaccination. Treatment with (A) anti-PD-1 or (B) anti-CTLA-4 therapeutically began at day 3 after tumor cell inoculation (arrow) with bioluminescence of mice bearing live tumors at 14 days after challenge (upper panels) and tumor volume kinetics (lower panels) (n = 5–6 per group). (C and D) Splenic and Ig LN mononuclear cells isolated at day 42 from anti-PD-1-treated groups and controls assessed for IFN-γ-production via ELISPOT after restimulation with NeoAg-pulsed BMDCs (n = 3 per group). All experiments were performed 2 or more times and data indicate mean ± SEM; (A and B, bioluminescence) **P < 0.01 and ***P < 0.001 (Student’s t test); †††P < 0.001 (1-way ANOVA and Dunnett’s posthoc test relative to polyI:C); (A and B, tumor volume) *P < 0.05, ***P < 0.001, and ****P < 0.0001 (2-way ANOVA and Dunnett’s posthoc test relative to polyI:C); †P < 0.05 and ††††P < 0.0001 (2-way ANOVA and Dunnett’s posthoc test relative to peptide mix boost + polyI:C); (C) *P < 0.05, **P < 0.01, ***P < 0.001, and ****P < 0.0001 (Student’s t test of data with SI > 2 and Poisson < 5%); †P < 0.05 (Student’s t test); (D) *P < 0.05 (Student’s t test).