Tumor-reactive T cell clonotype dynamics underlying clinical response to TIL therapy in melanoma.

Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) has inconsistent clinical responses. To better understand determinants of therapeutic success, we tracked TIL clonotypes from baseline tumors to ACT products and post-ACT blood and tumor samples in melanoma patients using single-cell RNA and T cell receptor (TCR) sequencing. Patients with clinical responses had baseline tumors enriched in tumor-reactive TILs, and these were more effectively mobilized upon in vitro expansion, yielding products enriched in tumor-specific CD8+ cells that preferentially infiltrated tumors post-ACT. Conversely, lack of clinical responses was associated with tumors devoid of tumor-reactive resident clonotypes and with cell products mostly composed of blood-borne clonotypes that persisted in blood but not in tumors post-ACT. Upon expansion, tumor-specific TILs lost tumor-associated transcriptional signatures, including exhaustion, and responders exhibited an intermediate exhausted effector state after TIL engraftment in the tumor, suggesting functional reinvigoration. Our findings provide insight into the nature and dynamics of tumor-specific clonotypes associated with clinical response to TIL-ACT, with implications for treatment optimization. [Display omitted] • Patients with clinical responses have baseline tumors enriched in tumor-reactive TILs • Tumor-reactive TILs are more effectively mobilized upon in vitro expansion • Non-responders' ACT products are mostly composed of blood-borne clonotypes • TIL-ACT promotes T cell reprogramming, suggesting functional reinvigoration Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) can be curative in melanoma but has inconsistent clinical responses. Chiffelle, Barras, et al. track TIL clonotypes in melanoma patients through ACT therapy and provide insight into the profiles and dynamics of tumor-specific clonotypes associated with clinical response and features related to non-responsiveness. [ABSTRACT FROM AUTHOR]