최정민 (Yale University School of Medicine)

한빛사논문

조회1,127

Yale University School of Medicine

CV File 231 kb

Nat. Commun., Published: 10 August 2018, 9, Article number: 3196 | https://doi.org/10.1038/s41467-018-05032-8 A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers

S.N. Gettinger¹, J. Choi², N. Mani^3,4, M.F. Sanmamed⁵, I. Datar^3,4, Ryan Sowell⁵, Victor Y. Du⁵, E. Kaftan^1,4, S. Goldberg¹, W. Dong², D. Zelterman ⁶, K. Politi^1,3, P. Kavathas ^5,7, S. Kaech⁵, X. Yu⁶, H. Zhao^2,6, J. Schlessinger⁸, R. Lifton², D.L. Rimm ^1,3, L. Chen ⁵, R.S. Herbst¹ & K.A. Schalper^1,3,4¹Medical Oncology and Yale Cancer Center, New Haven, CT 06511, USA. ²Department of Genetics, Yale School of Medicine, New Haven, CT 06511, USA. ³Department of Pathology, Yale School of Medicine, New Haven, CT 06511, USA.⁴ Translational Immuno-oncology Laboratory, Yale Cancer Center, New Haven, CT 06511, USA. ⁵ Immunobiology, Yale School of Medicine, New Haven, CT 06511, USA. ⁶ Yale School of Public Health, New Haven, CT 06511, USA. ⁷ Laboratory Medicine, Yale School of Medicine, New Haven, CT 06511, USA. ⁸Department of Pharmacology, Yale School of Medicine, New Haven, CT 06511, USA.

These authors contributed equally: S.N. Gettinger, J. Choi, N. Mani.

Correspondence to K. A. Schalper

Abstract

The biological determinants of sensitivity and resistance to immune checkpoint blockers are not completely understood. To elucidate the role of intratumoral T-cells and their association with the tumor genomic landscape, we perform paired whole exome DNA sequencing and multiplexed quantitative immunofluorescence (QIF) in pre-treatment samples from non-small cell lung carcinoma (NSCLC) patients treated with PD-1 axis blockers. QIF is used to simultaneously measure the level of CD3+ tumor infiltrating lymphocytes (TILs), in situ T-cell proliferation (Ki-67 in CD3) and effector capacity (Granzyme-B in CD3). Elevated mutational load, candidate class-I neoantigens or intratumoral CD3 signal are significantly associated with favorable response to therapy. Additionally, a “dormant” TIL signature is associated with survival benefit in patients treated with immune checkpoint blockers characterized by elevated TILs with low activation and proliferation. We further demonstrate that dormant TILs can be reinvigorated upon PD-1 blockade in a patient-derived xenograft model.

논문정보

형식Research article
게재일2018년 08월 (BRIC 등록일 2018-08-20)
연구진국외 연구진
분야 의약학 > 유전 및 유전체의학

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