Does Transcriptional Loss of HLA Cause Immunotherapy Resistance?

The development of resistance to immunotherapy is poorly understood and is detrimental to patients who relapse on multiple lines of treatment. Transcriptional downregulation of class 1 human leukocyte antigen (HLA) may contribute to the developed resistance of immunotherapies, including checkpoint inhibitors, and warrants further investigation, according to a study published in Nature Communications.

Recent cancer treatments have progressed significantly, increasing treatment choices to include immunotherapy and prolonging survival. However, similar to other cancer therapies, immunotherapy also develops resistance, leading to relapse and unresponsive patients.

Improving our understanding of resistance pathways is especially important to help identify newer effective treatments that can be used after relapse. In the past, genetic loss of an antigen present on CD8 cells was identified as the main reason for resistance, but recently, low antigen burden tumors have shown that a single HLA allele, particularly transcriptional downregulation, can be associated with the resistance to immunotherapy. To prove this assumption, the researchers treated 2 patients with Merkel cell carcinoma (MCC) with immunotherapy to determine if transcriptional suppression occurred.

Two patients with MCC were studied because MCC has high immunotherapy responsiveness, low mutational/neoepitope burden, and defined viral antigens that can be easily analyzed. The first patient was treated with autologous CD8 T cells followed by pembrolizumab and ipilimumab. Initially, the patient was responsive and achieved remission, but after 22 months, the patient relapsed on therapy. Upon performing RNA sequencing at the time of resistance, the selective loss of solely HLA-B was observed and found to be transcriptional and reversible. Infused CD8 T cells at relapse were absent from the infiltrating tumor and solely persisted in the periphery. For this patient, HLA-B was specifically downregulated even though it was not detected in a regular HLA-ABC immunohistochemistry. The downregulation of HLA-B was also reversible. After infusing interferon-γor 5-azacitadine, a hypomethylating agent, HLA-B transcriptional downregulation was reversed.

In the second patient, autologous CD8 T cells specific to HLA-A were used instead followed by avelumab, an anti—PD-L1. Similar to the first patient, the second patient also had a response followed by relapse at 18 months. At the point of relapse, selective transcriptional downregulation happened again, except this time at HLA-A, without changes to the HLA DNA sequence. Reversibility was not tested in this patient because tumor cultures were unavailable.

In both patients, selective transcriptional downregulation occurred, limiting itself to the targeted epitope. In the past, immunotherapy resistance was thought to be caused by genetic HLA loss, due to the deletion of HLA alleles and requiring new T-cell responses. However, transcriptional HLA loss is now something to consider where HLA suppression can be reversed through drug therapies as demonstrated from the first patient. Selective transcription loss is an important cause of immunotherapy resistance, and further evaluations may prompt the discovery of additional targetable therapies that may work for patients who relapse in difficult to treat cancers.

Reference

Paulson KG, Voillet V, McAfee MS, et al. Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA. Nat Commun. 2018;9(1):3868. doi: 10.1038/s41467-018-06300-3.