Clonal replacement of tumor-specific T cells following PD-1 blockade
Kathryn E Yost1, Ansuman T Satpathy2,3,4, Daniel K Wells5
1Center for Personal Dynamic Regulomes, Stanford University School of Medicine, Stanford, CA, USA.
Abstract:
Immunotherapies that block inhibitory checkpoint receptors on T cells have transformed the clinical care of patients with cancer1. However, whether the T cell response to checkpoint blockade relies on reinvigoration of pre-existing tumor-infiltrating lymphocytes or on recruitment of novel T cells remains unclear2-4. Here we performed paired single-cell RNA and T cell receptor sequencing on 79,046 cells from site-matched tumors from patients with basal or squamous cell carcinoma before and after anti-PD-1 therapy. Tracking T cell receptor clones and transcriptional phenotypes revealed coupling of tumor recognition, clonal expansion and T cell dysfunction marked by clonal expansion of CD8+CD39+ T cells, which co-expressed markers of chronic T cell activation and exhaustion. However, the expansion of T cell clones did not derive from pre-existing tumor-infiltrating T lymphocytes; instead, the expanded clones consisted of novel clonotypes that had not previously been observed in the same tumor. Clonal replacement of T cells was preferentially observed in exhausted CD8+ T cells and evident in patients with basal or squamous cell carcinoma. These results demonstrate that pre-existing tumor-specific T cells may have limited reinvigoration capacity, and that the T cell response to checkpoint blockade derives from a distinct repertoire of T cell clones that may have just recently entered the tumor.
Insights
Checkpoint blockade immunotherapy for cancer does not primarily reinvigorate existing tumor T cells. Instead, it expands novel T cell clones that recently infiltrated the tumor, suggesting a clonal replacement mechanism.
Area of Science:
- Immunology
- Oncology
- Genomics
Background:
- Immune checkpoint inhibitors (ICIs) targeting inhibitory receptors on T cells have revolutionized cancer treatment.
- A key question is whether ICI therapy revitalizes pre-existing tumor-infiltrating lymphocytes or recruits new ones.
Purpose of the Study:
- To investigate the origin and dynamics of T cell responses following anti-PD-1 therapy in cancer patients.
- To determine if ICI therapy leads to the expansion of pre-existing or novel T cell clones within tumors.
Main Methods:
- Paired single-cell RNA sequencing and T cell receptor sequencing were performed on 79,046 cells from matched tumors.
- Samples were collected from patients with basal or squamous cell carcinoma before and after anti-PD-1 treatment.
- T cell receptor clonotypes and transcriptional phenotypes were tracked to analyze T cell dynamics.
Main Results:
- Clonal expansion of CD8+CD39+ T cells, exhibiting markers of chronic activation and exhaustion, was observed.
- Expanded T cell clones originated from novel clonotypes, not pre-existing tumor-infiltrating lymphocytes.
- Clonal replacement was prominent in exhausted CD8+ T cells and observed in patients with basal or squamous cell carcinoma.
Conclusions:
- Pre-existing tumor-specific T cells may have limited capacity for reinvigoration under checkpoint blockade.
- The T cell response to anti-PD-1 therapy arises from a distinct repertoire of T cell clones, likely recent entrants to the tumor microenvironment.
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