한빛사논문
- 조회288
Noam Levin, Sanghyun P Kim, Charles A Marquardt, Nolan R Vale, Zhiya Yu, Sivasish Sindiri, Jared J Gartner, Maria Parkhurst, Sri Krishna, Frank J Lowery, Nikolaos Zacharakis, Lior Levy, Todd D Prickett, Tiffany Benzine, Satyajit Ray, Robert V Masi, Billel Gasmi, Yong Li, Rafiqul Islam, Alakesh Bera, Stephanie L Goff, Paul F Robbins and Steven A Rosenberg
Surgery Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
Correspondence to Dr Steven A Rosenberg; Dr Sanghyun P Kim; Dr Noam Levin
Abstract
Background: Tumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer treatments remains challenging because neoantigen-reactive T cells are often rare and exhausted, and ex vivo expansion can further reduce their frequencies. This complicates the identification of neoantigen-reactive T-cell receptors (TCRs) and the development of TIL products with high reactivity for patient treatment.
Methods: We tested whether TILs could be in vitro stimulated against neoantigens to achieve selective expansion of neoantigen-reactive TILs. Given their prevalence, mutant p53 or RAS were studied as models of human neoantigens. An in vitro stimulation method, termed "NeoExpand", was developed to provide neoantigen-specific stimulation to TILs. 25 consecutive patient TILs from tumors harboring p53 or RAS mutations were subjected to NeoExpand.
Results: We show that neoantigenic stimulation achieved selective expansion of neoantigen-reactive TILs and broadened the neoantigen-reactive CD4+ and CD8+ TIL clonal repertoire. This allowed the effective isolation of novel neoantigen-reactive TCRs. Out of the 25 consecutive TIL samples, neoantigenic stimulation enabled the identification of 16 unique reactivities and 42 TCRs, while conventional TIL expansion identified 9 reactivities and 14 TCRs. Single-cell transcriptome analysis revealed that neoantigenic stimulation increased neoantigen-reactive TILs with stem-like memory phenotypes expressing IL-7R, CD62L, and KLF2. Furthermore, neoantigenic stimulation improved the in vivo antitumor efficacy of TILs relative to the conventional OKT3-induced rapid TIL expansion in p53-mutated or KRAS-mutated xenograft mouse models.
Conclusions: Taken together, neoantigenic stimulation of TILs selectively expands neoantigen-reactive TILs by frequencies and by their clonal repertoire. NeoExpand led to improved phenotypes and functions of neoantigen-reactive TILs. Our data warrant its clinical evaluation.
논문정보
- Research article
- 2024년 05월 (BRIC 등록일 2024-06-04)
- 국외 연구진
- 생명과학 > 면역학
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