Tumor-reactive clonotype dynamics dictate clinical response to TIL therapy in melanoma [TCR-Seq]
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ABSTRACT: Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TILs) is effective in cancer patients, yet the profiles, specificity and dynamics of tumor clonotypes remain opaque. Using single-cell RNA/TCR-sequencing, clonotypes were tracked from baseline tumors to ACT products (ACTP) and post-ACT blood and tumor samples from 13 metastatic melanoma patients (NCT03475134). Furthermore, a predictor of tumor-reactive clonotypes was derived from the transcriptomic profiles of tumor-specific or bystander clones. Patients with clinical responses had tumors enriched in tumor-reactive TILs, preferentially expanding in-vitro to generate larger and more tumoricidal products and preferentially re-infiltrating tumors post-ACT. Conversely, lack of responses was associated with tumors devoid of tumor-reactive clonotypes and with cell products mostly composed of blood-borne clonotypes. The exhaustion state characterizing intratumoral tumor-reactive TILs was attenuated during in-vitro expansion and restored after tumor re-engraftment only in responders. Thus, tumor-reactive clonotypes drive clinical response to TIL therapy, providing insight to select patients or improve TILs’ culture.
ORGANISM(S): Homo sapiens
PROVIDER: GSE234352 | GEO | 2023/08/01
REPOSITORIES: GEO
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