A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers

S. N. Gettinger, Jaehyuk Choi, N. Mani, M. F. Sanmamed, I. Datar, Ryan Sowell, Victor Y. Du, E. Kaftan, S. Goldberg, W. Dong, D. Zelterman, K. Politi, P. Kavathas, S. Kaech, X. Yu, H. Zhao, J. Schlessinger, R. Lifton, D. L. Rimm, L. ChenR. S. Herbst, K. A. Schalper*

*Corresponding author for this work

Research output: Contribution to journalArticle

15 Citations (Scopus)

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.

Original languageEnglish (US)
Article number3196
JournalNature communications
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2018

Fingerprint

Tumor-Infiltrating Lymphocytes
phenotype
Lymphocytes
lymphocytes
Non-Small Cell Lung Carcinoma
lungs
Tumors
tumors
cancer
Cells
Phenotype
T-cells
Fluorescent Antibody Technique
Exome
T-Lymphocytes
Granzymes
effectors
DNA Sequence Analysis
Heterografts
sequencing

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Gettinger, S. N. ; Choi, Jaehyuk ; Mani, N. ; Sanmamed, M. F. ; Datar, I. ; Sowell, Ryan ; Du, Victor Y. ; Kaftan, E. ; Goldberg, S. ; Dong, W. ; Zelterman, D. ; Politi, K. ; Kavathas, P. ; Kaech, S. ; Yu, X. ; Zhao, H. ; Schlessinger, J. ; Lifton, R. ; Rimm, D. L. ; Chen, L. ; Herbst, R. S. ; Schalper, K. A. / A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers. In: Nature communications. 2018 ; Vol. 9, No. 1.
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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.",
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Gettinger, SN, Choi, J, Mani, N, Sanmamed, MF, Datar, I, Sowell, R, Du, VY, Kaftan, E, Goldberg, S, Dong, W, Zelterman, D, Politi, K, Kavathas, P, Kaech, S, Yu, X, Zhao, H, Schlessinger, J, Lifton, R, Rimm, DL, Chen, L, Herbst, RS & Schalper, KA 2018, 'A dormant TIL phenotype defines non-small cell lung carcinomas sensitive to immune checkpoint blockers', Nature communications, vol. 9, no. 1, 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. / Gettinger, S. N.; Choi, Jaehyuk; Mani, N.; Sanmamed, M. F.; Datar, I.; Sowell, Ryan; Du, Victor Y.; Kaftan, E.; Goldberg, S.; Dong, W.; Zelterman, D.; Politi, K.; Kavathas, P.; Kaech, S.; Yu, X.; Zhao, H.; Schlessinger, J.; Lifton, R.; Rimm, D. L.; Chen, L.; Herbst, R. S.; Schalper, K. A.

In: Nature communications, Vol. 9, No. 1, 3196, 01.12.2018.

Research output: Contribution to journalArticle

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AU - Gettinger, S. N.

AU - Choi, Jaehyuk

AU - Mani, N.

AU - Sanmamed, M. F.

AU - Datar, I.

AU - Sowell, Ryan

AU - Du, Victor Y.

AU - Kaftan, E.

AU - Goldberg, S.

AU - Dong, W.

AU - Zelterman, D.

AU - Politi, K.

AU - Kavathas, P.

AU - Kaech, S.

AU - Yu, X.

AU - Zhao, H.

AU - Schlessinger, J.

AU - Lifton, R.

AU - Rimm, D. L.

AU - Chen, L.

AU - Herbst, R. S.

AU - Schalper, K. A.

PY - 2018/12/1

Y1 - 2018/12/1

N2 - 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.

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