Journal
CANCER RESEARCH COMMUNICATIONS
Volume 2, Issue 7, Pages 739-753Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2767-9764.CRC-22-0050
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Funding
- Japan Society for the Promotion of Science (JSPS) [20H03694, 19K08744, 21K08314, 19K22574]
- Project for Cancer Research and Therapeutic Evolu- tion [P-CREATE] [18cm0106340h0001, 20cm0106502h0005, 21cm0106383]
- Practical Research for Innovative Cancer Control
- Japan Agency for Medical Research and Development (AMED) [19ck0106521h0001, 22ck0106723h0001]
- Fusion Oriented Research for disruptive Science and Technology [21-211033868]
- Japan Science and Technology Agency (JST)
- Chiba Prefecture Research Grant
- Naito Foundation
- Takeda Science Foundation
- Mochida Memorial Founda- tion
- Japanese Foundation for Multidisciplinary Treatment of Cancer Foundation
- KANAE Foundation for the Promo- tion of Medical Science
- Yasuda Memorial Foundation for Medicine
- MSD Life Science Foundation
- Kowa Life Science Foundation
- Uehara Memorial Foundation
- GSK Japan foundation
- Princess Takamatsu Cancer Re- search Fund
- Kato Memorial Bioscience Foundation
- Ono Medical Research Foundation
- Inamori Foundation
- Japan Respiratory Foundation
- Ube Industries Foundation
- KOTAI Biotechnologies Inc
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Some patients experience mixed response to immunotherapy, but the biological mechanisms and clinical significance remain unclear. Our study reveals that intertumoral heterogeneity alters characteristics of tumor-infiltrating lymphocytes (TILs) even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.
Some patients experience mixed response to immunotherapy, whose biological mechanisms and clinical impact have been obscure. We obtained two tumor samples from lymph node (LN) metastatic lesions in a same patient. Whole exome sequencing for the both tumors and single-cell sequencing for the both tumor-infiltrating lymphocytes (TIL) demonstrated a significant difference in tumor clonality and TILs' characteristics, especially exhausted T-cell clonotypes, although a close relationship between the tumor cell and T-cell clones were observed as a response of an overlapped exhausted T-cell clone to an overlapped neoantigen. To mimic the clinical setting, we generated a mouse model of several clones from a same tumor cell line. Similarly, differential tumor clones harbored distinct TILs, and one responded to programmed cell death protein 1 (PD-1) blockade but the other did not in this model. We further conducted cohort study (n = 503) treated with PD-1 blockade monotherapies to investigate the outcome of mixed response. Patients with mixed responses to PD-1 blockade had a poor prognosis in our cohort. Particularly, there were significant differences in both tumor and T-cell clones between the primary and LN lesions in a patient who experienced tumor response to anti-PD-1 mAb followed by disease progression in only LN metastasis. Our results underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.Significance: Several patients experience mixed responses to immunotherapies, but the biological mechanisms and clinical significance remain unclear. Our results from clinical and mouse studies underscore that intertumoral heterogeneity alters characteristics of TILs even in the same patient, leading to mixed response to immunotherapy and significant difference in the outcome.
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