Related Experiment Video

Updated: Aug 6, 2025

Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells
09:32

Multiplexed Immunofluorescence Analysis and Quantification of Intratumoral PD-1+ Tim-3+ CD8+ T Cells

Published on: February 8, 2018

14.7K

The molecular and functional landscape of resistance to immune checkpoint blockade in melanoma

Su Yin Lim1,2, Elena Shklovskaya1,2, Jenny H Lee1,2,3

  • 1Macquarie Medical School, Faculty of Medicine, Health and Human Sciences, Macquarie University, Sydney, NSW, Australia.

Nature Communications
|March 19, 2023
PubMed

Insights

Melanoma patients often resist immune checkpoint inhibitors. This study identifies three resistance mechanisms: lost antigen expression, disrupted antigen presentation, and immune cell exclusion, guiding new treatment strategies.

Area of Science:

  • Oncology
  • Immunology
  • Genetics

Background:

  • Immune checkpoint inhibitor (ICI) therapy has revolutionized melanoma treatment.
  • However, resistance to ICI therapies is a significant clinical hurdle, limiting treatment efficacy for many patients.

Purpose of the Study:

  • To comprehensively profile the mechanisms of resistance to immune checkpoint inhibitors in melanoma.
  • To identify distinct molecular and cellular programs driving immunotherapy resistance in melanoma patients.

Main Methods:

  • Analysis of short-term melanoma cell lines and matched tumor samples from patients progressing on ICIs.
  • Integration of genomic, transcriptomic, and high-dimensional flow cytometry profiling.
  • Functional assays to elucidate resistance mechanisms.

Main Results:

  • Identification of three distinct immunotherapy resistance programs in melanoma.
  • Program 1: Loss of wild-type antigen expression due to tumor-intrinsic interferon-gamma (IFNγ) signaling and melanoma de-differentiation.
  • Program 2: Disruption of antigen presentation affecting Major Histocompatibility Complex (MHC) expression through multiple mechanisms.
  • Program 3: Immune cell exclusion linked to phosphatase and tensin homolog (PTEN) loss.

Conclusions:

  • Compromised antigen production and presentation are dominant factors in melanoma ICI resistance.
  • Salvage strategies should focus on restoring MHC expression, stimulating innate immunity, and re-expressing wild-type differentiation antigens.

More Related Videos

Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine09:15

Experimental Melanoma Immunotherapy Model Using Tumor Vaccination with a Hematopoietic Cytokine

Published on: February 24, 2023

3.5K
Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology07:04

Identifying PD-1/PD-L1 Inhibitors with Surface Plasmon Resonance Technology

Published on: May 2, 2025

468

Related Concept Videos

Cytotoxic T Cells-mediated Immune Response01:27

Cytotoxic T Cells-mediated Immune Response

Cytotoxic T cells are a vital component of the immune system. They have the remarkable ability to identify and target antigens on infected or abnormal cells. These antigens often originate from intracellular pathogens such as viruses or abnormal proteins cancer cells produce.
Immunological surveillance is the ability of immune cells to monitor and eliminate infected cells with intracellular pathogens, neoplastically transformed cells, and cells with non-self antigens. Cytotoxic T cells and NK...
1.1K
Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
5.9K
Tumor Immunotherapy01:27

Tumor Immunotherapy

Immunotherapy is a treatment that boosts or manipulates the immune system to fight diseases, including cancer. For instance, by stimulating an immune response through vaccinations against viruses that cause cancers, like hepatitis B virus and human papillomavirus, these diseases can be prevented. Nonetheless, some cancer cells can avoid the immune system due to their rapid mutation and division. The immune response to many cancers involves three phases: elimination, equilibrium, and escape.
601
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
3.4K