Circulating T Cell Subpopulations Correlate With Immune Responses at the Tumor Site and Clinical Response to PD1 Inhibition in Non-Small Cell Lung Cancer

Abstract

Agents targeting the PD1–PDL1 axis have transformed cancer therapy. Factors that influence clinical response to PD1–PDL1 inhibitors include tumor mutational burden, immune infiltration of the tumor, and local PDL1 expression. To identify peripheral correlates of the anti-tumor immune response in the absence of checkpoint blockade, we performed a retrospective study of circulating T cell subpopulations and matched tumor gene expression in melanoma and non-small cell lung cancer (NSCLC) patients. Notably, both melanoma and NSCLC patients whose tumors exhibited increased inflammatory gene transcripts presented high CD4+ and CD8+ central memory T cell (CM) to effector T cell (Eff) ratios in blood. Consequently, we evaluated CM/Eff T cell ratios in a second cohort of NSCLC. The data showed that high CM/Eff T cell ratios correlated with increased tumor PDL1 expression. Furthermore, of the 22 patients within this NSCLC cohort who received nivolumab, those with high CM/Eff T cell ratios, had longer progression-free survival (PFS) (median survival: 91 vs. 215 days). These findings show that by providing a window into the state of the immune system, peripheral T cell subpopulations inform about the state of the anti-tumor immune response and identify potential blood biomarkers of clinical response to checkpoint inhibitors in melanoma and NSCLC.

Frequency of circulating CD8+CD73+T cells is associated with survival in nivolumab-treated melanoma patients

“…In melanoma patients expression of PD-1 on tumorinfiltrating CD8+T cells or on circulating T cells has been considered as a marker of tumor-reactive T cells [40][41][42][43]. More recently, it has been demonstrated that melanoma patients and NSCLC patients have a reduced percentage of circulating naïve T cells compared to controls [44]. To note, NSCLC patients with high central memory T cell (T CM ) to effector T cell (T Eff ) ratios, associated with inflamed tumors, showed longer progressionfree survival to nivolumab [44].…”

“…More recently, it has been demonstrated that melanoma patients and NSCLC patients have a reduced percentage of circulating naïve T cells compared to controls [44]. To note, NSCLC patients with high central memory T cell (T CM ) to effector T cell (T Eff ) ratios, associated with inflamed tumors, showed longer progressionfree survival to nivolumab [44]. Based on the associations of T cells states with response to immune checkpoint inhibitors, a detailed analysis of immune cells profile in melanoma tumors has been also reported [45].…”

The Immunoscore: Colon Cancer and Beyond

“…The use of novel biomarkers and assays has also become a clear need. In addition to biomarkers and methods directly involving the TME, the assessment of circulating components, whether blood-or bone marrow-associated, or combinations of thereof, seems to constitute promising tools (44)(45)(46)(47). In order to successfully demonstrate the correlation between vaccine-or spontaneously induced immune responses and clinical benefit, most studies rely on the use of wellrecognized, externally validated and harmonized immune assays (48).…”

Current issues and perspectives in PD-1 blockade cancer immunotherapy

“…High neutrophil/ lymphocyte ratio (NLR), which is typically measured in conventional blood tests, is associated with poor prognosis in cytotoxic T lymphocyte antigen-4 (CTLA-4) antibodytreated patients with malignant melanoma [33] and in PD-1 antibody-treated patients with various cancer [34,35]. CD4 + T cells increase in the periphery is reported to be related to good response after nivolumab treatment [36,37]. Cells release extracellular exosomes containing their surface molecules [38,39].…”