Blockade of LAG-3 and PD-1 leads to co-expression of cytotoxic and exhaustion gene modules in CD8+ T cells to promote antitumor immunity

Cell. 2024 Aug 8;187(16):4373-4388.e15. doi: 10.1016/j.cell.2024.06.036.

Abstract

Relatlimab (rela; anti-LAG-3) plus nivolumab (nivo; anti-PD-1) is safe and effective for treatment of advanced melanoma. We designed a trial (NCT03743766) where advanced melanoma patients received rela, nivo, or rela+nivo to interrogate the immunologic mechanisms of rela+nivo. Analysis of biospecimens from this ongoing trial demonstrated that rela+nivo led to enhanced capacity for CD8+ T cell receptor signaling and altered CD8+ T cell differentiation, leading to heightened cytotoxicity despite the retention of an exhaustion profile. Co-expression of cytotoxic and exhaustion signatures was driven by PRDM1, BATF, ETV7, and TOX. Effector function was upregulated in clonally expanded CD8+ T cells that emerged after rela+nivo. A rela+nivo intratumoral CD8+ T cell signature was associated with a favorable prognosis. This intratumoral rela+nivo signature was validated in peripheral blood as an elevated frequency of CD38+TIM3+CD8+ T cells. Overall, we demonstrated that cytotoxicity can be enhanced despite the retention of exhaustion signatures, which will inform future therapeutic strategies.

Keywords: CD8(+) T cell transcriptional profiles; LAG-3; PD-1; T cell exhaustion; advanced melanoma; antitumor immunity; checkpoint blockade; combination immunotherapy; inhibitory receptors.

Publication types

  • Clinical Trial, Phase II

MeSH terms

  • Antigens, CD / genetics
  • Antigens, CD / metabolism
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • CD8-Positive T-Lymphocytes* / immunology
  • CD8-Positive T-Lymphocytes* / metabolism
  • Cell Differentiation
  • Cytotoxicity, Immunologic
  • High Mobility Group Proteins
  • Humans
  • Immune Checkpoint Inhibitors / pharmacology
  • Immune Checkpoint Inhibitors / therapeutic use
  • Lymphocyte Activation Gene 3 Protein* / antagonists & inhibitors
  • Melanoma* / drug therapy
  • Melanoma* / genetics
  • Melanoma* / immunology
  • Nivolumab / pharmacology
  • Nivolumab / therapeutic use
  • Positive Regulatory Domain I-Binding Factor 1 / genetics
  • Positive Regulatory Domain I-Binding Factor 1 / metabolism
  • Programmed Cell Death 1 Receptor* / antagonists & inhibitors
  • Signal Transduction

Substances

  • Antigens, CD
  • Basic-Leucine Zipper Transcription Factors
  • High Mobility Group Proteins
  • Immune Checkpoint Inhibitors
  • Lag3 protein, human
  • Lymphocyte Activation Gene 3 Protein
  • Nivolumab
  • PDCD1 protein, human
  • Positive Regulatory Domain I-Binding Factor 1
  • Programmed Cell Death 1 Receptor
  • TOX protein, human