Vaccination generates functional progenitor tumor-specific CD8 T cells and long-term tumor control

Sep 21, 2026

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Immune checkpoint blockade can produce durable remission only in a subset of advanced-cancer patients, prompting interest in cancer vaccines that may reprogram tumor immunity long term. This study used a clinically relevant genetic mouse model with sporadic oncogenic transformation in hepatocytes to compare tumor-specific CD8 T-cell differentiation in early versus late lesions and to test vaccination, alone or with ICB, on liver cancer progression and survival.

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CategoryResearch & Report

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Introduction

Open access Original research Vaccination generates functional progenitor tumor-specific CD8 T cells and long-term tumor control Carlos R Detrés Román,1 Megan M Erwin,2 Michael W Rudloff,2 Frank Revetta,3 Kristen A Murray,4 Natalie R Favret,2 Jessica J Roetman,1 Joseph T Roland,5 Mary K Washington,3 Mary Philip 6,7 To cite: Detrés Román CR, Erwin MM, Rudloff MW, et al. Vaccination generates functional progenitor tumor-specific CD8 T cells and long-term tumor control. Journal for ImmunoTherapy of Cancer 2024;12:e009129 . doi:10 . 1136/ jitc-2024-009129 ► Additional supplemental material is published online only. To view, please visit the journal online ([https://doi.org/10.1136/](https://doi.org/10.1136/)[ ](https://doi.org/10.1136/)[jitc-2024-009129](jitc-2024-009129)) . Accepted 30 August 2024 © Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. For numbered affiliations see end of article. Correspondence to Dr Mary Philip; [mary.philip@vumc.org](mary.philip@vumc.org) ABSTRACT Background Immune checkpoint blockade (ICB) therapies are an important treatment for patients with advanced cancers; however, only a subset of patients with certain types of cancer achieve durable remission. Cancer vaccines are an attractive strategy to boost patient immune responses, but less is known about whether and how immunization can induce long-term tumor immune reprogramming and arrest cancer progression. We developed a clinically relevant genetic cancer mouse model in which hepatocytes sporadically undergo oncogenic transformation. We compared how tumorspecific CD8 T cells (TST) differentiated in mice with early sporadic lesions as compared with late lesions and tested how immunotherapeutic strategies, including vaccination and ICB, impact TST function and liver cancer progression. Methods Mice with a germline floxed allele of the SV40 large T antigen (TAG) undergo spontaneous recombination and activation of the TAG oncogene, leading to rare early cancerous TAG-expressing lesions that inevitably progress to established liver cancer. We assessed the immunophenotype (CD44, PD1, TCF1, and TOX expression) and function (TNFα and IFNγ cytokine production) of tumor/TAG-specific CD8 T cells in mice with early and late liver lesions by flow cytometry. We vaccinated mice, either alone or in combination with ICB, to test whether these immunotherapeutic interventions could stop liver cancer progression and improve survival. Results In mice with early lesions, a subset of TST were PD1+ TCF1+ TOX − and could produce IFNγ while TST present in mice with late liver cancers were PD1+ TCF1lo/− TOX+ and unable to make effector cytokines. Strikingly, vaccination with attenuated TAG epitopeexpressing Listeria monocytogenes (LMTAG) blocked liver cancer development and led to a population of TST that were PD1-heterogeneous, TCF1+ TOX − and polyfunctional cytokine producers. Vaccine-elicited TCF1+TST could selfrenew and differentiate, establishing them as progenitor TST. In contrast, ICB administration did not slow cancer progression or improve LMTAG vaccine efficacy. Conclusion Vaccination, but not ICB, generated a population of functional progenitor TST and halted cancer progression in a clinically relevant model of sporadic liver cancer. In patients with early cancers or at high risk of cancer recurrence, immunization may be the most effective strategy. WHAT IS ALREADY KNOWN ON THIS TOPIC | ⇒ Immunotherapy, including immune checkpoint blockade and cancer vaccines, fails to induce longterm remissions in most patients with cancer.
WHAT THIS STUDY ADDS | | --- | | ⇒ Hosts with early lesions but not hosts with advanced cancer retain a progenitor TCF1+tumor-specific CD8 T cell (TST) population. This population can be therapeutically exploited by vaccination, but not immune checkpoint blockade, to block tumor progression.
HOW THIS STUDY MIGH

FAQs

Which intervention improved survival and halted tumor progression?

Vaccination with attenuated TAG-epitope–expressing Listeria monocytogenes blocked liver cancer development and generated functional progenitor TST, whereas ICB did not slow progression or improve vaccine efficacy.

Sep 21, 2026

Uploaded by Rowan