The researchers explain how some lung tumors evade immunotherapy
MYC oncogenic activation, an important gene in cancer development, has the potential to identify lung cancer patients who may respond poorly to immunotherapy.
This is the main conclusion of a study recently published by a research team led by Montse Sanchez-Cespedes, principal investigator from the Cancer Genetics group at the Josep Carreras Leukemia Research Institute in Spain. Their findings highlight key contributors to poor response and suggest a novel approach to selecting patients who would benefit from immune checkpoint (ICB) blockade or require alternative treatments well in advance.
ICB therapy has become the standard treatment for lung cancer because the results are generally positive. To date, high PD-L1 protein levels have been the primary means of predicting a positive treatment response. However, many lung cancer tumors have high protein levels and still fail to respond to immunotherapy, while others with similarly low protein levels respond.
Identifying which patients will respond strongly ahead of time can save valuable time and help patients live longer, healthier lives.
ICB treatment inhibits the action of PD-L1 and its partner PD1, to increase the action of the immune system against tumor cells. Both of these proteins are part of a natural system for avoiding autoimmunity, with PD-L1 normally present in cell membranes (including cancer cells) and, through interaction with PD-1, present in immune cells, preventing overreactions. immune system that can damage the organism. In the context of tumors, this causes the immune system not to kill cancer cells, which is why ICB treatment tries to block this contact.
On the other hand, tumors were found with low levels of PD-L1. Without this immune-limiting mechanism, how would they avoid strong immune attacks? In a recent publication in the scientific journal Cell Reports Medicine, a team led by Sanchez-Cespedes reports that many tumors with low PD-L1 have developed genetic strategies that circumvent the action of interferon gamma against tumor cells. Gamma interferon is a powerful stimulator of the immune response secreted by immune cells and, avoiding its action, tumor cells cannot be killed by the immune system.
New clinical trials
One of the genetic strategies found in tumor cells is the activation of the MYC oncogene, which leads to a cascade of events that prevents the action of interferon gamma within the cell. Experimental results suggest this could be a strong and reliable predictor of response to ICB in cancer patients, because tumors with genetic activation of MYC are associated with a poorer prognosis after treatment with ICB.
The reported new findings may inspire new clinical trials to assess whether MYC status can be a better marker than PD-L1 abundance for selecting patients for ICB or similar treatment, and make a difference in the clinical management of lung cancer in the near future.
This study is a joint effort with researchers from the Josep Carreras Institute (IJC-CERCA), Vic University, Trias i Pujol German Hospital and the Center for Regulation of Genomics (CRG). It is partially funded by the Spanish Ministry of Economy and Asociación Española Contra el Cáncer (AECC).