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J. Immunother. Cancer, Mar 12 2024, 12 (3) e008001 | https://doi.org/10.1136/jitc-2023-008001
rhIL-7-hyFc and hIL-2/TCB2c combination promotes an immune-stimulatory tumor microenvironment that improves antitumor efficacy of checkpoint inhibitors
Minji Lee1, Sun-Kyoung Im1, Seungtae Baek1, Mankyu Ji1, Miyoung Kim1, Eun Ju Lee1, Seung Taek Ji1, Sara Ferrando-Martinez2, Alexandra Wolfarth2, Jun-Young Lee3, Daeun Kim3 and Donghoon Choi1
1Research Institute of NeoImmuneTech, Co., Ltd, Pohang, Korea (the Republic of)
2NeoImmuneTech, Inc, Rockville, Maryland, USA
3Selecxine, Pohang, Korea (the Republic of)
Correspondence to Dr Donghoon Choi
Abstract
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).
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.
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 CD39
highTIM-3
+ Treg cells. Most importantly, rhIL-7-hyFc increases infiltration of a CD62L
+Ly108
+ early progenitor population of exhausted CD8
+ T cells (T
PEX), which may retain long-term proliferation capacity and replenish functional effector CD8
+ T cells. hIL-2/TCB2c induces differentiation of CD62L
+Ly108
+ T
PEX rapidly into CD101
+ terminally differentiated subsets (terminally exhausted T cell (T
EX term)). Our study also demonstrates that rhIL-7-hyFc significantly enhances the proliferation rate of T
PEX 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.
rhIL-7-hyFc can expand and maintain the progenitor pool of exhausted CD8
+ T cells, whereas hIL-2/TCB2c promotes their differentiation into T
EX term. Together, this induces an immune-stimulatory TME that improves the efficacy of checkpoint blockade.
논문정보
- Research article
- 2024년 03월 (BRIC 등록일 2024-03-13)
- 국내(교신)+국외 연구진
- 생명과학 > 면역학
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