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 4

MHC restriction and functional interplay of CD4+ and CD8+ T cell vaccine-derived epitopes.

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MHC restriction and functional interplay of CD4+ and CD8+ T cell vaccine...
(A) H129Q 15/10-mer peptides derived from Mut_48. (B and C) Naive C3H/HeJ mice compared with animals that received a 1 × 107 irradiated SCC VII cell and 50 μg polyI:C immunization followed by a 5 × 105 live SCC VII-Luc/GFP cell challenge at day 14. Day 28 splenic/Ig LN (B) CD8+ T cells and (C) CD4+ T cells cocultured with Mut_48-derived minimal peptide-pulsed BMDCs for quantification of IFN-γ-producing cells via ELISPOT ± blocking antibodies against I-Ak, I-Ek, and H-2Kk (n = 3 per group). (D) IEDB NetMHCpan (v4.0) MHC I predictions of minimal peptide binding to murine H-2Kk. (E) Mut_48.10 and Mut_48.5 epitope schematic. (F) CD8+ T cell ELISPOT responses against Pool_9, Pool_10, Pool_11, Pool_13, Pool_14, and Pool_15 clustered by IFN-γ production (positive versus negative). Represented are IEDB NetMHCpan (v4.0) MHC I predictions of minimal peptide binding to murine H-2Kk. (G) C3H/HeJ mice vaccinated with 50 μg polyI:C alone or in combination with 5 μg Mut_48.5 or Mut_48.10 peptides in a booster regimen 21 days apart followed by challenge with 5 × 105 live SCC VII-Luc/GFP cells 31 days after primary vaccination. Day 14 bioluminescence and tumor volume kinetics (n = 5–6 per group). All experiments were performed 2 or more times and data indicate mean ± (B, C, and G) SEM or (F) median; (G, bioluminescence) *P < 0.05 and **P < 0.01 (Student’s t test); ††P < 0.01 (1-way ANOVA and Dunnett’s posthoc test relative to polyI:C); (G, tumor volume) *P < 0.05 and ***P < 0.001 (2-way ANOVA and Dunnett’s posthoc test relative to polyI:C); (B and C) *P < 0.05, **P < 0.01, and ****P < 0.0001 (Student’s t test of data with SI > 2 and Poisson < 5%); (B) ††P < 0.01 (Student’s t test); (C) ††P < 0.01 (1-way ANOVA and multiple comparison Tukey’s posthoc test).