Transcriptional programs of tumor infiltrating T-cells provide insight into mechanisms of immune response and new targets for immunotherapy

Abstract

Early 2015 marked the first major clinical success of immunotherapy in lung cancer, resulting in the FDA approval of nivolumab (an anti-PD-1 antibody) for metastatic squamous non-small cell lung cancer (NSCLC). A little over a year later, two additional PD-1 blocking agents were approved, atezolizumab and pembrolizumab, f o r u s e i n t h e t r e a t m e n t o f m e t a s t a t i c N S C L C . Pembrolizumab was approved as a first line therapeutic option if a patient's tumor was found to contain at least 50% of tumor cells expressing PD-L1. While immunotherapeutic advancements in lung cancer are promising, response rates to anti-PD-1 therapy in NSCLC have been poor, ranging from 15-50% (1-3), even when prospectively screening tumors for PD-L1 expression before therapeutic intervention. Likewise, clinical response has been observed for anti-PD-1 agents independent of a tumor's baseline PD-L1 status (4-6), which further complicates clinical decision making in the assessment of optimal therapy for NSCLC. A great deal of additional research is necessary to determine the best use of checkpoint inhibitors in lung cancer and the best set of tumor-immune features for determining durable clinical response.The recent publication by Ganesan et al. in Nature Immunology (7) highlights the need for a deeper understanding of the immunological state of lung tumors to determine how the immune landscape of lung tumors may predispose patients for better or worse outcomes. The authors investigated the molecular features associated with robust anti-tumor immune responses by extracting tumorinfiltrating and adjacent-normal T cells from surgically resected NSCLC specimens and utilizing RNA-seq to analyze the transcriptional programs of these immune cells. Marked differences in the transcriptional landscape were found in tumor infiltrating T cells when compared to their adjacent-normal T cell counterparts. Likewise, they characterized similar transcriptional program profiles in tumor-infiltrating T cells derived from head and neck squamous cell carcinoma (HNSCC), ultimately validating their T cell findings and further suggesting that a core set of regulatory programs may define tumor-infiltrating leukocytes across multiple tumor types. Major players in the active transcriptional programing of tumor-infiltrating T cells appeared to be related to T cell exhaustion, cell-cycle regulation, and T cell receptor activation. Most significantly, exhaustion signatures were found to be upregulated in the tumor-infiltrating T cells, a gene set containing the clinically relevant immunotherapeutic targets such as PD-1, CTLA-4, and TIM-3.The authors also noted significant heterogeneity in the expression of these clinically relevant T cell exhaustion targets among the tumor-infiltrating T cells, which they highlighted may account for the person-to-person variability