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ORIGINAL RESEARCH article

Front. Immunol.
Sec. Cancer Immunity and Immunotherapy
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1477171

Enabling immune checkpoint blockade efficacy in T-lymphopenia by restoring CD8 T cell dynamics with IL-7 cytokine therapy

Provisionally accepted
Yeon-Woo Kang Yeon-Woo Kang 1Donghoon Choi Donghoon Choi 2Dain Moon Dain Moon 1Kun-Joo Lee Kun-Joo Lee 1Youngsik Oh Youngsik Oh 1Jaehyuk Yang Jaehyuk Yang 1Siheon Jeong Siheon Jeong 1Uni Park Uni Park 1Sun-Kyoung Im Sun-Kyoung Im 2Se Hwan Yang Se Hwan Yang 2Seung-Woo Lee Seung-Woo Lee 1*
  • 1 Pohang University of Science and Technology, Pohang, Republic of Korea
  • 2 Research Institute of NeoImmuneTech, Inc., Pohang, Republic of Korea

The final, formatted version of the article will be published soon.

    T-lymphopenia (TLP) is a frequently observed condition in cancer patients, often exacerbated by conventional chemo/radiotherapy, which impairs the efficacy of subsequent immune checkpoint blockade (ICB) therapy. This study aimed to understand the impact of TLP on ICB responsiveness and explore potential therapeutic strategies to enhance antitumor immunity. Using mouse models mimicking clinical TLP, we observed that the antitumor efficacy of anti-PD-1 therapy was severely impaired in TLP, depending on the degree of TLP and the immunogenicity of the tumors. TLP mice showed a significant reduction in systemic CD8 T cells but stable intratumoral CD8 T cell numbers, suggesting maintained tumor infiltration despite systemic downregulation. Crucially, TLP led to a shift in the composition of tumor-infiltrating lymphocytes, with a decrease in PD-1 + tumor-reactive CD8 T cells and an increase in PD-1 -bystander cells. This reduction in PD-1 + cells was linked to impaired clonal expansion in tumor-draining lymph nodes. To counteract these effects, we introduced recombinant IL-7 cytokine therapy (rhIL-7-hyFc), which effectively restored systemic T cell counts, enhanced PD-1 + CD8 T cell proliferation within tumors, and increased the population of stem-like progenitor cells. The combination of rhIL-7-hyFc and anti-PD-1 therapy resulted in significant tumor regression and improved mouse survival. Our findings highlight the critical role of IL-7 in reshaping the CD8 T cell landscape to improve ICB efficacy in TLP conditions, proposing a sequential therapeutic approach: conventional therapy to reduce tumor burden and enhance immunogenicity, followed by IL-7 therapy to restore and rejuvenate CD8 T cells, culminating in effective ICB treatment.

    Keywords: T-lymphopenia1, Treatment-related lymphopenia2, Interleukin-73, Chemo/radiotherapy4, Tumor-infiltrating lymphocytes5, Tumor-reactive CD8 T cells6, Stemlike exhausted CD8 T cells7

    Received: 07 Aug 2024; Accepted: 29 Nov 2024.

    Copyright: © 2024 Kang, Choi, Moon, Lee, Oh, Yang, Jeong, Park, Im, Yang and Lee. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Seung-Woo Lee, Pohang University of Science and Technology, Pohang, Republic of Korea

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