Immune escape mechanisms associated with tumor recurrence after adoptive cell transfer immunotherapy.

Background: Adoptive cell transfer immunotherapy (ACT) with tumor infiltrating lymphocytes (TILs) results in unprecedented rates of durable clinical responses but some patients initially responding achieve only a temporary disease remission before tumor recurrence. Methods: Disease relapse in a case of metastatic melanoma experiencing tumor recurrence after complete response to treatment with TILs was characterized at the cellular and molecular level using primary tumor cell lines and tumor infiltrating lymphocytes derived from metastatic lesions resected at different time points. Results: Multiple mechanisms linked to tumor-intrinsic evolutional phenomena associated with tumor re-growth despite durable persistence of peripheral antitumor responses were identified. Tumor-cell intrinsic alterations led to both impaired immune sensitivity and universally reduced immune recognition associated with multiple defects in antigen processing machinery, but not to antigen loss or increased expression of immune suppressive molecules such as PD-L1. In addition, cell lines from tumor recurrence were characterized by increased in vivo malignancy independent of immune response sensitivity, in the absence of new known melanoma driver mutations. Conclusions: Data from this study brings direct evidence that tumor cell evolutionary mechanisms responsible for immune escape, and associated with disease recurrence in human metastatic tumors after effective immunotherapies targeting multiple antigens, are extraordinarily complex and multifactorial. Future strategies to extend duration of responses to immunotherapy should consider targeting this complexity