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Tumor Transplantation for Assessing the Dynamics of Tumor-Infiltrating CD8+ T Cells in Mice
Published on: June 12, 2021
Tumor-reactive T cell clonotype dynamics underlying clinical response to TIL therapy in melanoma
Johanna Chiffelle1, David Barras1, Rémy Pétremand1
1Ludwig Institute for Cancer Research, Lausanne Branch, Department of Oncology, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Agora Cancer Research Center, Lausanne, Switzerland; Center for Cell Therapy, CHUV-Ludwig Institute, Lausanne, Switzerland.
Abstract:
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.
Insights
Adoptive cell therapy (ACT) with tumor-infiltrating lymphocytes (TILs) shows variable results. Responders had more tumor-reactive TILs initially, which were better expanded and infiltrated tumors post-therapy, unlike non-responders.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Adoptive cell therapy (ACT) using in vitro expanded tumor-infiltrating lymphocytes (TILs) shows inconsistent clinical responses in melanoma patients.
- Understanding the factors driving therapeutic success is crucial for optimizing TIL-ACT.
Purpose of the Study:
- To investigate the clonal dynamics of TILs from baseline tumors to post-ACT samples.
- To identify characteristics of TIL clonotypes associated with clinical response to TIL-ACT in melanoma.
Main Methods:
- Single-cell RNA and T cell receptor (TCR) sequencing were employed to track TIL clonotypes.
- Analysis of baseline tumors, ACT products, and post-ACT blood and tumor samples from melanoma patients.
Main Results:
- Clinical responders had baseline tumors enriched in tumor-reactive TILs, which were effectively expanded and led to tumor-specific CD8+ cell infiltration post-ACT.
- Non-responders' tumors lacked tumor-reactive TILs, and their cell products were dominated by blood-borne clonotypes persisting in blood but not tumors.
- Tumor-specific TILs lost exhaustion signatures upon expansion, with responders showing an intermediate exhausted effector state post-engraftment, suggesting functional reinvigoration.
Conclusions:
- Tumor-reactive TIL clonotype dynamics are critical for clinical response to TIL-ACT.
- Identifying and expanding tumor-specific TILs may improve TIL-ACT efficacy.
- Findings offer insights for optimizing TIL-ACT strategies in melanoma.
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