Mutations Associated with No Durable Clinical Benefit to Immune Checkpoint Blockade in Non-S-Cell Lung Cancer

Guangsheng Zhu1,2, Dian Ren1,2, Xi Lei1,2

  • 1Department of Lung Cancer Surgery, Tianjin Medical University General Hospital, Tianjin 300050, China.

Cancers
|April 3, 2021
PubMed

Insights

FAT1 gene mutations may predict non-small-cell lung cancer (NSCLC) response to immune checkpoint blockade (ICB) therapy. This finding could help identify patients who will not benefit from ICB, enabling personalized immunotherapy strategies.

Area of Science:

  • Oncology
  • Immunotherapy
  • Genetics

Background:

  • Immune checkpoint blockade (ICB) shows promise in non-small-cell lung cancer (NSCLC), but only 20% of patients respond.
  • Lack of responsiveness to ICB is a significant challenge in cancer immunotherapy.

Purpose of the Study:

  • To identify gene mutations associated with no durable clinical benefit (NDB) to ICBs in NSCLC patients.
  • To evaluate the predictive value of identified mutations for ICB therapy efficacy.

Main Methods:

  • Analysis of four public NSCLC cohorts (2986 patients).
  • Screening 158 NSCLC patients with NDB to ICBs for gene mutations using Cox regression.
  • Assessment of PD-L1 expression, tumor mutation burden (TMB), neoantigen load, and immune cell infiltration.

Main Results:

  • FAT1 and KEAP1 mutations correlated with NDB in NSCLC patients.
  • FAT1 mutation was identified as a predictive biomarker for ICB efficacy, while KEAP1 served as a prognostic biomarker.
  • FAT1 mutations were linked to higher TMB and reduced CD8+ T-cell infiltration.
  • A prognostic model incorporating PD-L1, TMB, smoking status, treatment, and FAT1 mutation showed high accuracy (AUCs 0.763-0.871).

Conclusions:

  • FAT1 mutation may serve as a predictive biomarker for NSCLC patients unresponsive to ICBs.
  • An FAT1 mutation-based model can help screen suitable NSCLC patients for ICB, advancing individualized immunotherapy.

Related Concept Videos

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.
818
lncRNA - Long Non-coding RNAs02:39

lncRNA - Long Non-coding RNAs

In humans, more than 80% of the genome gets transcribed. However, only around 2% of the genome codes for proteins. The remaining part produces non-coding RNAs which includes ribosomal RNAs, transfer RNAs, telomerase RNAs, and regulatory RNAs, among other types. A large number of regulatory non-coding RNAs have been classified into two groups depending upon their length – small non-coding RNAs, such as microRNA, which are less than 200 nucleotides in length, and long non-coding RNA...
9.3K
Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against...
8.0K