Processing Escapes: an Alternative Explanation for Immune Therapy Resistance

Aim Immunotherapy is one of the most sophisticated approaches in cancer therapy. Most prominent agents in usage are immune checkpoint inhibitors including αPD1/αPDL1 antibodies. Although their successful application has been proven in many cancers, 60% of patients show developments of therapy resistance. We consider escape mutations in relation with deficient tumor antigen processing (processing escapes) as one possible explanation. We investigated their existence and impact in a highly diverse collective of lung cancer patients.
Methods Targeted panel sequencing was performed on 70 patients suffering from pulmonary neuroendocrine lung cancers (NELCs) and mutations influencing proteasomal processing were identified by in silico prediction. In addition, about 400 patient data from the TCGA data base were also taken for control purposes (lung adenocarcinoma and squamous-cell carcinoma) The association between processing escapes and expression of immune factors in lung cancer has been analyzed. Regression models were used to calculate overall survival in dependence of mutation load.
Results Processing escapes were broadly identified in all tumor entities. According to correlation analysis, about 80% of all processing escapes were significantly associated with reduced expression of granzyme B, CD40L and CD20, referring to an overall reduced immune response against the tumor. The mutation load does also not differ between high- and low-grade tumors. Survival analysis revealed significantly impaired survival in correlation with high mutation load.
Conclusion Processing escapes may become a helpful tool to predict outcome of immune therapied patients. Thereby, it hopefully helps to identify patients with bad prognosis, providing them alternative therapeutic strategies.