rhIL-7-hyFc and hIL-2/TCB2c combination promotes an immune-stimulatory tumor microenvironment that improves antitumor efficacy of checkpoint inhibitors
© 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..
BACKGROUND: Recombinant human interleukin (rhIL)-7-hyFc (efineptakin alfa; NT-I7) is a potent T-cell amplifier, with two IL-7 molecules fused to IgD/IgG4 elements. rhIL-7-hyFc promotes extensive infiltration of CD8+ T cells into the tumor, concurrently increasing the numbers of intratumoral PD-1+CD8+ T cells. The hIL-2/TCB2 complex (SLC-3010) inhibits tumor growth by preferential activation of CD122 (IL-2Rβ)high CD8+ T cells and natural killer cells, over regulatory T cells (Tregs). We investigated the underlying mechanisms of rhIL-7-hyFc and hIL-2/TCB2c antitumor activity and the potential synergistic efficacy, specifically focusing on tumor-specific CD8+ cells within the tumor and the tumor-draining lymph nodes (tdLN).
METHODS: MC38 and CT26 tumor-bearing mice were administered with 10 mg/kg rhIL-7-hyFc intramuscularly and 0.9 mg/kg hIL-2/TCB2c intravenously. Anti-PD-1 monoclonal antibody was administered intraperitoneally three times at 3-day intervals at a dose of 5 mg/kg. Tumor volume was measured to assess efficacy. To compare the composition of immune cells between each monotherapy and the combination therapy, we analyzed tumors and tdLNs by flow cytometry.
RESULTS: Our data demonstrate that the combination of rhIL-7-hyFc and hIL-2/TCB2c increases efficacy and generates an immune-stimulatory tumor microenvironment (TME). The TME is characterized by an increased infiltration of tumor-specific CD8+ T cells, and a decreased frequency of CD39highTIM-3+ Treg cells. Most importantly, rhIL-7-hyFc increases infiltration of a CD62L+Ly108+ early progenitor population of exhausted CD8+ T cells (TPEX), which may retain long-term proliferation capacity and replenish functional effector CD8+ T cells. hIL-2/TCB2c induces differentiation of CD62L+Ly108+ TPEX rapidly into CD101+ terminally differentiated subsets (terminally exhausted T cell (TEX term)). Our study also demonstrates that rhIL-7-hyFc significantly enhances the proliferation rate of TPEX in the tdLNs, positively correlating with their abundance within the tumor. Moreover, rhIL-7-hyFc and hIL-2/TCB2c can overcome the limited therapeutic effectiveness of PD-1 blockade, culminating in the complete regression of tumors.
CONCLUSIONS: rhIL-7-hyFc can expand and maintain the progenitor pool of exhausted CD8+ T cells, whereas hIL-2/TCB2c promotes their differentiation into TEX term. Together, this induces an immune-stimulatory TME that improves the efficacy of checkpoint blockade.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:12 |
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| Enthalten in: |
Journal for immunotherapy of cancer - 12(2024), 3 vom: 12. März |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Lee, Minji [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 14.03.2024 Date Revised 15.03.2024 published: Electronic Citation Status MEDLINE |
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| doi: |
10.1136/jitc-2023-008001 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Lee, Minji |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a rhIL-7-hyFc and hIL-2/TCB2c combination promotes an immune-stimulatory tumor microenvironment that improves antitumor efficacy of checkpoint inhibitors |
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| 500 | |a Date Revised 15.03.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 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. | ||
| 520 | |a BACKGROUND: Recombinant human interleukin (rhIL)-7-hyFc (efineptakin alfa; NT-I7) is a potent T-cell amplifier, with two IL-7 molecules fused to IgD/IgG4 elements. rhIL-7-hyFc promotes extensive infiltration of CD8+ T cells into the tumor, concurrently increasing the numbers of intratumoral PD-1+CD8+ T cells. The hIL-2/TCB2 complex (SLC-3010) inhibits tumor growth by preferential activation of CD122 (IL-2Rβ)high CD8+ T cells and natural killer cells, over regulatory T cells (Tregs). We investigated the underlying mechanisms of rhIL-7-hyFc and hIL-2/TCB2c antitumor activity and the potential synergistic efficacy, specifically focusing on tumor-specific CD8+ cells within the tumor and the tumor-draining lymph nodes (tdLN) | ||
| 520 | |a METHODS: MC38 and CT26 tumor-bearing mice were administered with 10 mg/kg rhIL-7-hyFc intramuscularly and 0.9 mg/kg hIL-2/TCB2c intravenously. Anti-PD-1 monoclonal antibody was administered intraperitoneally three times at 3-day intervals at a dose of 5 mg/kg. Tumor volume was measured to assess efficacy. To compare the composition of immune cells between each monotherapy and the combination therapy, we analyzed tumors and tdLNs by flow cytometry | ||
| 520 | |a RESULTS: Our data demonstrate that the combination of rhIL-7-hyFc and hIL-2/TCB2c increases efficacy and generates an immune-stimulatory tumor microenvironment (TME). The TME is characterized by an increased infiltration of tumor-specific CD8+ T cells, and a decreased frequency of CD39highTIM-3+ Treg cells. Most importantly, rhIL-7-hyFc increases infiltration of a CD62L+Ly108+ early progenitor population of exhausted CD8+ T cells (TPEX), which may retain long-term proliferation capacity and replenish functional effector CD8+ T cells. hIL-2/TCB2c induces differentiation of CD62L+Ly108+ TPEX rapidly into CD101+ terminally differentiated subsets (terminally exhausted T cell (TEX term)). Our study also demonstrates that rhIL-7-hyFc significantly enhances the proliferation rate of TPEX in the tdLNs, positively correlating with their abundance within the tumor. Moreover, rhIL-7-hyFc and hIL-2/TCB2c can overcome the limited therapeutic effectiveness of PD-1 blockade, culminating in the complete regression of tumors | ||
| 520 | |a CONCLUSIONS: rhIL-7-hyFc can expand and maintain the progenitor pool of exhausted CD8+ T cells, whereas hIL-2/TCB2c promotes their differentiation into TEX term. Together, this induces an immune-stimulatory TME that improves the efficacy of checkpoint blockade | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a CD8-positive T-lymphocytes | |
| 650 | 4 | |a cytokines | |
| 650 | 4 | |a drug therapy, combination | |
| 650 | 4 | |a immune checkpoint inhibitors | |
| 650 | 4 | |a tumor microenvironment | |
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| 650 | 7 | |a 3K3WC6MT6P |2 NLM | |
| 650 | 7 | |a Programmed Cell Death 1 Receptor |2 NLM | |
| 650 | 7 | |a Immunologic Factors |2 NLM | |
| 650 | 7 | |a Recombinant Fusion Proteins |2 NLM | |
| 650 | 7 | |a Interleukin-7 |2 NLM | |
| 700 | 1 | |a Im, Sun-Kyoung |e verfasserin |4 aut | |
| 700 | 1 | |a Baek, Seungtae |e verfasserin |4 aut | |
| 700 | 1 | |a Ji, Mankyu |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Miyoung |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Eun Ju |e verfasserin |4 aut | |
| 700 | 1 | |a Ji, Seung Taek |e verfasserin |4 aut | |
| 700 | 1 | |a Ferrando-Martinez, Sara |e verfasserin |4 aut | |
| 700 | 1 | |a Wolfarth, Alexandra |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Jun-Young |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Daeun |e verfasserin |4 aut | |
| 700 | 1 | |a Choi, Donghoon |e verfasserin |4 aut | |
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