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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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 3

Deconvolution of CD4+ and CD8+ T cell responses to SCC VII-derived neoantigens.

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Deconvolution of CD4+ and CD8+ T cell responses to SCC VII-derived neoan...
(A–C) C3H/HeJ mice vaccinated with 50 μg polyI:C alone or in combination with 5 μg solubilized 20-mers in a booster regimen 21 days apart. All sets of mice were challenged with 5 × 105 live SCC VII-Luc/GFP cells 31 days after primary vaccination. Individual (A) Mut_44, Mut_48, Mut_61, Mut_65, or Mut_67 long peptides, (B) Mut_48 versus WT_48, and (C) Mut_72 and Mut_73 long peptides reported as bioluminescence of mice at 14 days after challenge and tumor volume kinetics (n = 5–6 per group). (D) Groups of naive C3H/HeJ mice compared with animals that received a 1×107 irradiated SCC VII cell and 50 μg polyI:C immunization and later challenge assessed for the presence of IFN-γ-producing CD4+ and CD8+ T cells sorted from spleens and Ig LNs at day 28 after immunization 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-C, bioluminescence) **P < 0.01 and ***P < 0.001 (Student’s t test); †P < 0.05 and ††P < 0.01 (1-way ANOVA and Dunnett’s posthoc test relative to polyI:C); (A–C, tumor volume) **P < 0.01 and ****P < 0.0001 (2-way ANOVA and Dunnett’s posthoc test relative to polyI:C); (D) *P < 0.05, **P < 0.01, and ****P < 0.0001 (Student’s t test of data with SI > 2 and Poisson < 5%).