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Evaluation of Tumor-infiltrating Leukocyte Subsets in a Subcutaneous Tumor Model
Published on: April 13, 2015
GZMK expression within activated intratumoral T-cell subsets reflects differentiation efficiency and predicts
Cem M Sievers1,2, Tian-Gen Chang3, Yvette Robbins4
1Head and Neck Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. cem.sievers@nih.gov.
Abstract:
Neoadjuvant immunotherapies (NITs) have demonstrated clinical benefit in head and neck carcinoma and other cancers by enhancing T cell-mediated anti-tumor immunity. However, disease recurrence remains a major challenge in a significant proportion of patients. Characterization of T cell dynamics underlying NIT outcomes may lead to improved treatment strategies. Here, we identify baseline intratumoral T cell differentiation efficiency as a predictor of response to NIT. Clonal analysis of tumor-emergent T cells post-treatment revealed granzyme K (GZMK) expression within differentiated subsets as a marker of recent differentiation. Efficient pre-treatment differentiation of GZMK+ progenitor T cells toward activated effectors predicts increased treatment-induced tumor regression. Consistently, pre-treatment tumor-infiltrating T cell clones predominantly adopt either exhausted, tissue-resident memory-like, or peripherally enriched GZMK+ progenitor states, implicating impaired intratumoral differentiation in limited anti-tumor immunity at baseline. Together, our findings demonstrate that GZMK+ T cell profiles reflect baseline anti-tumor immunocompetence and offer a clinically actionable biomarker for predicting immunotherapy response. NCT04247282, ClinicalTrails.gov, registered 1/30/2020 and NCT03429036, ClinicalTrails.gov, registered 11/06/2020.
Insights
Neoadjuvant immunotherapies improve cancer outcomes by boosting T cell immunity. This study identifies T cell differentiation efficiency as a key predictor of treatment response, offering a new biomarker for immunotherapy effectiveness.
Area of Science:
- Immunology
- Oncology
- Cellular Biology
Background:
- Neoadjuvant immunotherapies (NITs) show promise in treating head and neck carcinoma and other cancers by enhancing T cell-mediated anti-tumor immunity.
- Despite benefits, disease recurrence persists in many patients, highlighting the need for strategies to optimize treatment outcomes.
- Understanding T cell dynamics is crucial for improving NIT efficacy.
Purpose of the Study:
- To identify baseline intratumoral T cell differentiation efficiency as a predictor of response to neoadjuvant immunotherapies.
- To characterize T cell dynamics post-treatment and correlate them with treatment outcomes.
- To establish GZMK+ T cell profiles as a biomarker for predicting immunotherapy response.
Main Methods:
- Clonal analysis of tumor-emergent T cells following neoadjuvant immunotherapy.
- Assessment of granzyme K (GZMK) expression as a marker of recent T cell differentiation.
- Evaluation of pre-treatment T cell differentiation states (exhausted, tissue-resident memory-like, GZMK+ progenitor) in tumor-infiltrating lymphocytes.
Main Results:
- Efficient pre-treatment differentiation of GZMK+ progenitor T cells into activated effectors predicts greater treatment-induced tumor regression.
- Pre-treatment tumor-infiltrating T cell clones were found in exhausted, tissue-resident memory-like, or GZMK+ progenitor states.
- Impaired intratumoral T cell differentiation at baseline is associated with limited anti-tumor immunity.
Conclusions:
- Baseline intratumoral T cell differentiation efficiency, particularly of GZMK+ progenitor T cells, is a significant predictor of response to neoadjuvant immunotherapy.
- GZMK+ T cell profiles serve as a clinically actionable biomarker reflecting baseline anti-tumor immunocompetence.
- These findings offer insights into optimizing immunotherapy strategies by assessing T cell differentiation status prior to treatment.
