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 8

Identification of CD4+ and CD8+ T cell subsets in tumors and peripheral lymphoid organs.

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Identification of CD4+ and CD8+ T cell subsets in tumors and peripheral ...
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 Mut_48 peptide at day 10 after challenge. Select groups of mice also received anti-PD-1 at days 10, 13, and 16. TIL, tumor-draining Ig LN, and spleens isolated from day 17 tumor-bearing mice gated on total CD4+ and CD8+ T cells (n = 5 per group). (A) High-dimensional FACS UMAP of all organs and treatments colored by CD4+ versus CD8+ T cell type with (B) total T cell positioning annotated by organ (upper panel) and TIL alone annotated by treatment (lower panel). (C) Identified T cell metaclusters and (D) expression profiles of selected phenotypic markers associated with each metacluster in UMAP space. (E) Pseudotime trajectory of CD8+ T cells using Wishbone analysis with CD8+ Tn (0.0 = start) to Tex-term and short-lived Teff (1.0 = end) differentiation displayed and branches in development converged. Distribution of CD62L (Tn and Tmem), TCF-1/SLAMF6 (Tprec/prog and Tmem), GzmB/CX3CR1/CD44/Ki-67 (Tex-int and Teff), and TOX/PD-1 (Tex-int and Tex-term) represented as expression (upper panel) and rate of change (lower panel). (F) Representative FACS profiles of metaclusters of interest from all organs converged. All experiments were performed 2 or more times.