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Checkpoint Blockade Resistance Linked to Shifts in Neoantigen-Causing Mutations

NEW YORK (GenomeWeb) – A new study suggests some cancers can jettison a large proportion of mutations recognized by the immune system as they become resistant to immune checkpoint blockade treatments targeting PD1 and/or CTLA4.

As they reported recently in Cancer Discovery, researchers from Johns Hopkins University used a combination of tumor exome sequencing and T-cell receptor analysis to search for clues to checkpoint inhibitor resistance in four individuals with non-small cell lung cancer and one head and neck cancer patient treated with the PD1 inhibitor nivolumab alone or in combination with the anti-CTLA4 treatment ipilimumab.

By comparing pre-treatment tumor samples with those taken after resistance developed, the team found that resistant clones typically contained fewer mutations targeted by the immune system, known as mutation-associated neoantigens. In particular, the group saw signs that neoantigens may have been weeded out through T immune cell removal of certain sub-clones or loss of chromosomal regions with rampant neoantigens.

"Our findings offer evidence about how cancer cells evolve during immunotherapy," senior author Victor Velculescu, a program leader at Johns Hopkins' Bloomberg-Kimmel Institute for Cancer Immunotherapy, said in a statement. "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."

Starting with a group of 42 individuals with NSCLC who were treated with anti-PD1 or anti-PD1 and anti-CTLA4 treatment, the researchers followed four individuals who developed resistance to these treatments. They also analyzed neoantigen profiles in pre-treatment and resistant samples from an individual with head and neck squamous cell carcinoma.

Using the Illumina HiSeq 2000 or 2500 instruments, the team sequenced protein-coding regions of the genome captures captured with Agilent SureSelect kits from pre-treatment and resistant tumors for all four individuals.

In general, the analysis revealed an uptick in somatic alterations in the resistant tumor samples. But despite the enhanced mutational load, some antigen-producing mutations appeared to have disappeared in tumors that had become resistant to anti-PD1 or anti-PD1 and anti-CTLA4 antibodies. In particular, the researchers saw as many as 18 specific neoantigen-coding genes that were present in pre-treatment samples but missing once resistance was established.

The immune-dodging loss of neoantigens appeared to have been accomplished through the immune-mediated removal of sub-clones with mutation-associated neoantigens or, in some cases, via the introduction of new mutations that effectively remove neoantigen-related sequences, the researchers reported.

Nevertheless, the individuals' immune system remained poised to curb the activity of cells that did contain the initial neoantigens. The team found that T cells collected from the blood of at least three checkpoint inhibitor-resistant patients displayed clonal expansion in response to peptides produced from neoantigens eliminated after treatment resistance.

The study's authors cautioned that additional research will be needed to evaluate neoantigen patterns and resistance in larger sets of individuals treated with checkpoint inhibitors and in those who acquire resistance to such treatments over longer periods of time. 

"While larger studies will be required to study the full spectrum of therapeutic resistance to immunotherapy, our findings provide insights into the relatively rapid dynamics of neoantigen gains and losses during therapy and reveal a potential mechanism of resistance for at least a fraction of these patients," they wrote.