Study Identifies How Lung Tumors Acquire Immunotherapy Resistance

Non-small cell lung cancer (NSCLC) can acquire resistance to immune checkpoint blockade agents through evolutionary culling of tumor clones harboring the mutations for cell surface neoantigens that are recognized by patients’ immune T cells, according to a small study published in Cancer Discovery.

“When the cancer cells shed these mutations, they discard the evidence that would normally lead them to be recognized by the body’s protective immune cells,” said corresponding study author and Professor of Oncology Victor Velculescu, MD, PhD, of the Sidney Kimmel Comprehensive Cancer Center and the Bloomberg-Kimmel Institute for Cancer Immunotherapy at Johns Hopkins University School of Medicine in Baltimore.

Nearly half of patients with NSCLC suffer acquired tumor resistance to checkpoint inhibitors but the underlying mechanisms have remained a “mystery,” Dr. Velculescu noted.

The researchers used whole-exome sequencing and next-generation sequencing to study four patients’ NSCLC tumors and one patient’s head and neck cancer before initiation of immune checkpoint blockade therapy with the anti-PD-1 agent nivolumab with or without the anti-CTLA4 agent ipilimumab, and again after the tumors had acquired treatment resistance.

They found that acquired tumor resistance was accompanied by the loss of between seven and 18 neoantigen-encoding tumor mutations. Neoantigen loss “occurred through elimination of tumor subclones or through deletion of chromosomal regions” that contained mutations, they concluded.

“In some instances, we found that chromosomes in the cancer cells’ nuclei were missing an entire arm containing these mutated genes,” Dr. Velculescu noted.

The researchers subsequently cultured the neoantigen proteins missing from immunotherapy-resistant tumors with immune cells from patient blood samples and found that up to six of the mutant neoantigens were indeed recognized by immune T cells. Neoantigens associated with HELB, SCL26A7 and PGAP1 mutations were associated with clonal T-cell expansion, for example.

The findings “imply that widening the breadth of neoantigen reactivity may mitigate the development of acquired resistance” to immunotherapies, the authors concluded.

“Checkpoint inhibitors are one of the most exciting recent advances for cancers, but the mechanism by which most patients become resistant to these therapies has been a mystery,” he said. “Our findings offer evidence about how cancer cells evolve during immunotherapy.”