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Loss of tumor suppressors promotes inflammatory tumor microenvironment and enhances LAG3+T cell mediated immune

Sara Zahraeifard1, Zhiguang Xiao1, Jae Young So1

  • 1Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Nature Communications
|July 12, 2024
PubMed

Insights

Loss of tumor suppressors (TS) creates an immune-suppressive tumor microenvironment, hindering cancer immunotherapy. Targeting immune checkpoints like LAG3 offers a new strategy for treating cancers with inactivated TS.

Area of Science:

  • Oncology
  • Immunology
  • Cancer Biology

Background:

  • Immune checkpoint blockade (ICB) faces challenges with low response rates, relapse, and resistance in cancer treatment.
  • Loss of tumor suppressors (TS) can promote an immune-suppressive tumor microenvironment and is linked to increased immune checkpoint inhibitor expression.

Purpose of the Study:

  • To identify tumor suppressors that regulate the immune microenvironment and immune checkpoint mediator expression.
  • To investigate the therapeutic potential of targeting specific immune checkpoints in tumors with inactivated tumor suppressors.

Main Methods:

  • Utilized in vivo CRISPR/Cas9 loss-of-function screening to identify key tumor suppressors.
  • Analyzed chromatin accessibility and inflammatory pathways (IL6-JAK3-STAT3/6) upon TS loss.
  • Assessed the efficacy of combined LAG3 and PD-L1 blockade in preclinical triple-negative breast cancer (TNBC) models.

Main Results:

  • Identified NF1, TSC1, and TGF-β RII as tumor suppressors regulating immune composition.
  • Loss of these TSs alters chromatin accessibility, enhances inflammatory pathways, and promotes an immune-suppressive landscape with increased LAG3+ T cells.
  • Simultaneous blockade of LAG3 and PD-L1 inhibited metastasis in preclinical models of NF1-, TSC1-, or TGF-β RII-deficient TNBC.

Conclusions:

  • Tumor suppressors play a critical role in modulating the immune compartment and metastasis through non-cell-autonomous mechanisms.
  • Targeting LAG3, in combination with PD-L1, presents a promising therapeutic strategy for patients with cancers harboring inactivated NF1, TSC1, or TGF-β RII.

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