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Updated: Sep 27, 2025
Analysis of Human T Cell Activity in an Allogeneic Co-Culture Setting of Pre-Treated Tumor Cells
Published on: March 7, 2025
Distinct Immune Gene Programs Associated with Host Tumor Immunity, Neoadjuvant Chemotherapy, and Chemoimmunotherapy
Pedro Rocha1,2, Jiexin Zhang3, Raquel Laza-Briviesca4
1Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Purpose:
Our understanding of the immunopathology of resectable non-small cell lung cancer (NSCLC) is still limited. Here, we explore immune programs that inform of tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in localized NSCLC.
Experimental Design:
Targeted immune gene sequencing using the HTG Precision Immuno-Oncology panel was performed in localized NSCLCs from three cohorts based on treatment: naïve (n = 190), neoadjuvant chemotherapy (n = 38), and neoadjuvant chemoimmunotherapy (n = 21). Tumor immune microenvironment (TIME) phenotypes were based on the location of CD8+ T cells (inflamed, cold, excluded), tumoral PD-L1 expression (<1% and ≥1%), and tumor-infiltrating lymphocytes (TIL). Immune programs and signatures were statistically analyzed on the basis of tumoral PD-L1 expression, immune phenotypes, and pathologic response and were cross-compared across the three cohorts.
Results:
PD-L1-positive tumors exhibited increased signature scores for various lymphoid and myeloid cell subsets (P < 0.05). TIME phenotypes exhibited disparate frequencies by stage, PD-L1 expression, and mutational burden. Inflamed and PD-L1+/TILs+ NSCLCs displayed overall significantly heightened levels of immune signatures, with the excluded group representing an intermediate state. A cytotoxic T-cell signature was associated with favorable survival in neoadjuvant chemotherapy-treated NSCLCs (P < 0.05). Pathologic response to chemoimmunotherapy was positively associated with higher expression of genes involved in immune activation, chemotaxis, as well as T and natural killer cells (P < 0.05 for all). Among the three cohorts, chemoimmunotherapy-treated NSCLCs exhibited the highest scores for various immune cell subsets including T effector and B cells (P < 0.05).
Conclusions:
Our findings highlight immune gene programs that may underlie host tumor immunity and response to neoadjuvant chemotherapy and chemoimmunotherapy in resectable NSCLC.
Insights
This study reveals key immune gene programs influencing tumor immunity and treatment response in resectable non-small cell lung cancer (NSCLC). Understanding these immune signatures can guide neoadjuvant chemotherapy and chemoimmunotherapy strategies for NSCLC patients.
Area of Science:
- Oncology
- Immunology
- Genetics
Background:
- The immunopathology of resectable non-small cell lung cancer (NSCLC) remains incompletely understood.
- Identifying immune factors is crucial for optimizing treatment strategies in localized NSCLC.
Purpose of the Study:
- To explore immune gene programs that define tumor immunity.
- To investigate their role in response to neoadjuvant chemotherapy and chemoimmunotherapy in localized NSCLC.
Main Methods:
- Targeted immune gene sequencing was performed on NSCLC samples from three treatment cohorts: treatment-naïve, neoadjuvant chemotherapy, and neoadjuvant chemoimmunotherapy.
- Tumor immune microenvironment (TIME) phenotypes were characterized by CD8+ T cell infiltration, PD-L1 expression, and tumor-infiltrating lymphocytes (TILs).
- Immune signatures were statistically analyzed based on PD-L1 expression, TIME phenotypes, and pathologic response.
Main Results:
- PD-L1-positive tumors showed significantly higher immune signature scores for lymphoid and myeloid subsets.
- TIME phenotypes varied by stage, PD-L1 expression, and mutational burden, with inflamed and PD-L1+/TILs+ NSCLCs exhibiting heightened immune signatures.
- A cytotoxic T-cell signature correlated with better survival in patients receiving neoadjuvant chemotherapy, while chemoimmunotherapy response was linked to genes involved in immune activation and specific immune cell types.
Conclusions:
- Immune gene programs identified in this study are associated with host tumor immunity.
- These findings provide insights into predicting and improving responses to neoadjuvant chemotherapy and chemoimmunotherapy in resectable NSCLC.
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