Tumor microenvironment changes leading to resistance of immune checkpoint inhibitors in metastatic melanoma and strategies to overcome resistance

Bhargavi Pulluri, Abhijeet Kumar, Montaser Shaheen, Joanne M Jeter, Srinath Sundararajan

Research output: Contribution to journalReview article

16 Citations (Scopus)

Abstract

Immunotherapy with checkpoint inhibitors targeting CTLA-4 and/or PD-1 receptors independent of the BRAF mutational status and targeted therapy with BRAF and MEK inhibitors in BRAF V600 mutated patients have taken the forefront of advanced melanoma treatment. The main advantage of immunotherapy is its ability to provide durable responses in a subset of patients. However, significant proportions of patients either do not respond or have progression after initial response to immunotherapies. Multiple changes in the tumor microenvironment, such as down regulation of immune checkpoint ligands by tumor, alteration in interferon signaling, and activation of alternate immune suppressive pathways, have been identified as possible reasons for failure of immune checkpoint therapy. Here, we review the resistance mechanisms adopted by cancer cells to checkpoint inhibitor therapy and targeted therapy. In addition, we focus on the available and emerging evidence on tumor microenvironment modulation by BRAF/MEK inhibitor therapy and its role in improving responses to checkpoint inhibitor therapy.

Original languageEnglish (US)
Pages (from-to)95-102
Number of pages8
JournalPharmacological Research
Volume123
DOIs
StatePublished - Sep 1 2017
Externally publishedYes

Fingerprint

Tumor Microenvironment
Melanoma
Immunotherapy
Mitogen-Activated Protein Kinase Kinases
Therapeutics
Programmed Cell Death 1 Receptor
Interferons
Neoplasms
Down-Regulation
Ligands

Keywords

  • BRAF inhibitors
  • Combination immunotherapy
  • Immune checkpoint inhibitors
  • Immunotherapy
  • MEK inhibitors
  • Outcomes
  • Resistance mechanisms
  • Targeted therapy
  • Tumor micro-environment

ASJC Scopus subject areas

  • Pharmacology

Cite this

Tumor microenvironment changes leading to resistance of immune checkpoint inhibitors in metastatic melanoma and strategies to overcome resistance. / Pulluri, Bhargavi; Kumar, Abhijeet; Shaheen, Montaser; Jeter, Joanne M; Sundararajan, Srinath.

In: Pharmacological Research, Vol. 123, 01.09.2017, p. 95-102.

Research output: Contribution to journalReview article

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abstract = "Immunotherapy with checkpoint inhibitors targeting CTLA-4 and/or PD-1 receptors independent of the BRAF mutational status and targeted therapy with BRAF and MEK inhibitors in BRAF V600 mutated patients have taken the forefront of advanced melanoma treatment. The main advantage of immunotherapy is its ability to provide durable responses in a subset of patients. However, significant proportions of patients either do not respond or have progression after initial response to immunotherapies. Multiple changes in the tumor microenvironment, such as down regulation of immune checkpoint ligands by tumor, alteration in interferon signaling, and activation of alternate immune suppressive pathways, have been identified as possible reasons for failure of immune checkpoint therapy. Here, we review the resistance mechanisms adopted by cancer cells to checkpoint inhibitor therapy and targeted therapy. In addition, we focus on the available and emerging evidence on tumor microenvironment modulation by BRAF/MEK inhibitor therapy and its role in improving responses to checkpoint inhibitor therapy.",
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