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

Nat Commun. 2018 Aug 10;9(1):3196. doi: 10.1038/s41467-018-05032-8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Antibodies, Blocking / pharmacology
  • Carcinogenesis / drug effects
  • Carcinogenesis / genetics
  • Carcinoma, Non-Small-Cell Lung / immunology*
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Cell Proliferation / drug effects
  • Cytotoxicity, Immunologic / drug effects
  • Histocompatibility Antigens Class I / metabolism
  • Humans
  • Lung Neoplasms / immunology*
  • Lung Neoplasms / pathology
  • Lymphocyte Activation / immunology
  • Lymphocytes, Tumor-Infiltrating / drug effects
  • Lymphocytes, Tumor-Infiltrating / immunology*
  • Lymphocytes, Tumor-Infiltrating / pathology
  • Male
  • Mice, Inbred NOD
  • Mice, SCID
  • Mutant Proteins / chemistry
  • Mutation / genetics
  • Nicotiana
  • Peptides / chemistry
  • Phenotype
  • Programmed Cell Death 1 Receptor / metabolism
  • Reproducibility of Results
  • Survival Analysis

Substances

  • Antibodies, Blocking
  • Histocompatibility Antigens Class I
  • Mutant Proteins
  • PDCD1 protein, human
  • Peptides
  • Programmed Cell Death 1 Receptor