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 11

Tethered CD4+ T cell helper epitopes optimize checkpoint blockade and CTL-mediated SCC VII tumor destruction via a CD40-dependent mechanism.

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Tethered CD4+ T cell helper epitopes optimize checkpoint blockade and CT...
(A) C3H/HeJ mice injected with 5 × 105 live SCC VII-Luc/GFP cells and given 50 μg polyI:C alone or in combination with 5 μg full-length Mut_48 peptide at day 10 after challenge (black arrow). Peptide-treated mice also received anti-PD-1 at days 10, 13, and 16 (red arrow). The immunotherapy cycle repeated at day 24 (gray box). CD4+ and CD8+ T cells were depleted 1 day before each immunotherapy cycle (green arrow), and anti-CD40 was delivered as indicated (blue arrow) with resultant tumor volume kinetics (n = 6 per group). (B) Tumor-bearing C3H/HeJ mice delivered 50 μg polyI:C alone or combined with 5 μg PADRE(X), Mut_48.10, mixed PADRE(X) and Mut_48.10, or tethered PADRE(X)-AAA-Mut_48.10 peptide at day 10 after challenge (black arrow) and anti-PD-1 (red arrow) as in A with resultant tumor volume kinetics (n = 5-6 per group). All experiments were performed 2 or more times and data indicate mean ± SEM; (A and B) **P < 0.01 and ****P < 0.0001 (2-way ANOVA and Dunnett’s posthoc test relative to polyI:C); †P < 0.05, ††P < 0.01, and †††P < 0.001 (2-way ANOVA and Dunnett’s posthoc test relative to Mut_48 + polyI:C + anti-PD-1 + anti-CD4 or anti-CD8 [blue groups]).