Increased CD3+ T cells with a low FOXP3+/CD8+ T cell ratio can predict anti-PD-1 therapeutic response in non-small cell lung cancer patients

Hyojin Kim, Hyun Jung Kwon, Yeon Bi Han, Soo Young Park, Eun Sun Kim, Se Hyun Kim, Yu Jung Kim, Jong Seok Lee, Jin Haeng Chung

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

To determine whether tumor microenvironments affect the clinical response to anti-PD-1 therapy in non-small cell lung cancer, we investigated the expression level of PD-L1 and tumor infiltrating lymphocytes and elucidate their predictive role. Thirty-eight pretreatment and two post-treatment specimens from 36 advanced, treatment-refractory non-small cell lung cancer patients who underwent PD-1 blockade therapy were analyzed. PD-L1 expression by tumor cells and the distribution of CD3, CD8, CD4, FOXP3 and PD-1 positive tumor infiltrating lymphocytes were immunohistochemically assessed and counted using digital image analyzer. CD3+ and CD8+ T cells were distributed more in PD-L1 positive group compared to PD-L1 negative group. Conversely, EGFR mutant group showed fewer CD3+ T cells than EGFR-naïve group. The patients in the clinical benefit group with PD-1 blockade showed a higher number of CD3+, CD8+ T cells and a higher CD8+/CD3+ T cell ratio (p = 0.003, p = 0.001, and p = 0.042) and a lower FOXP3+/CD8+ T cell ratio compared to non-responders (p = 0.001). In multivariate logistic regression analysis, increased CD3+ T cell infiltration and low FOXP3+/CD8+ T cell ratio were found to be independent predictors of clinical benefit with PD-1 blockade (p = 0.014 and p = 0.03, respectively). Using receiver operating characteristic curves, levels of CD3+ T cells and FOXP3+/CD8+ T cell ratio that provide the best distinguishing point between responder versus non-responder to PD-1 blockade were 617.5/mm 2 and 25%, respectively (p = 0.007 and p = 0.003). Considering that 1 mm 2 is about 5 high power fields (HPF), a good response to the PD-1 blockade can be expected when the number of CD3 T cells is observed to be 120 per HPF and when CD8+ T cells and FOXP3+ T cells are present at a ratio greater than 4:1. Tumor infiltrating lymphocytes might become a promising biomarker as an independent predictive factor of response to PD-1 blockade that may also guide therapeutic decisions.

Original languageEnglish
Pages (from-to)367-375
Number of pages9
JournalModern Pathology
Volume32
Issue number3
DOIs
StatePublished - 1 Mar 2019

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