Research reveals a mechanism of acquired resistance to immunotherapy in lung cancer

A multidisciplinary team has identified genetic alterations that occur during immunotherapy and underlie treatment resistance in lung cancer.

The study, titled "Impaired HLA Class I Antigen Processing and Presentation as a Mechanism of Acquired Resistance to Immune Checkpoint Inhibitors in Lung Cancer," is published first 12 Oct. 2017 in the journal Cancer Discovery.

Immunotherapy presents a new treatment option for cancer patients, particularly for those who do not respond to targeted therapy. In addition, immunotherapy generally results in fewer side effects than chemotherapy does. Many immunotherapy drugs target immune checkpoints to enhance the immunity against cancer cells -- these drugs are called immune checkpoint inhibitors. For example, pembrolizumab, a humanized antibody against the checkpoint protein PD-1, was approved by the FDA for metastatic non-small cell lung cancer (NSCLC). Currently, pembrolizumab is also used treat certain other cancers.

However, for various types of treatments including immunotherapy, resistance is the biggest challenge. Some cancer patients have primary resistance, meaning that they do not respond to treatment initially. Besides, most patients eventually develop acquired resistance after an initial response to treatment.

For this study, Dr. Katerina Politi, associate professor at Yale University, and colleagues investigated acquired resistance. They collected tissue samples from NSCLC patients before they received immune checkpoint inhibitors and after their tumors became resistant to the treatment. Combining genetic analysis with other methods, they identified a mutation in the B2M protein in one patient.

In the next step, the researchers carried out a series of experiments in patient-derived xenografts and in a mouse lung cancer model. The results demonstrated that downregulation of B2M indeed correlates with resistance to immune checkpoint inhibitors in lung cancer.

B2M is a portion of the HLA complex, and is synthesized and shed by many cells, particularly lymphocytes. This protein is proposed as a potential regulator of the immune system. Dr. Politi noted that without B2M, T cells become unable to recognize tumor cells. Therefore, B2M disruption helps lung cancer cells to escape the effect of immunotherapy.

Collectively, these data suggest that genetic mutations in B2M may confer resistance to immune checkpoint inhibitors. The study reveals a mechanism of acquired resistance to immunotherapy in lung cancer and may lead to ways to overcome resistance to immunotherapy.

In addition to researchers from Yale University, researchers from CIMA and Clinica Universidad de Navarra, Rockefeller University, and Harvard Medical School also participated in the study.
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