Prognostic significance of tumor infiltrating lymphocytes on first-line pembrolizumab efficacy in advanced non-small cell lung cancer

Abstract

Aim Tumor-infiltrating lymphocytes (TILs) in the tumor and stroma are expected to accurately predict the efficacy of programmed death-1 (PD-1) blockade therapy. However, little is known about the prognostic significance of TILs in first-line PD-1 therapy. We assessed TILs in patients with advanced or metastatic non-small cell lung cancer (NSCLC) treated with pembrolizumab in the palliative setting. Methods Multiplex immunohistochemistry staining of TILs (CD4, CD8, Foxp3, and PD-1) and immunohistochemical staining of CK and PD-L1 in the tumor and stroma was performed in tumor specimens of 107 NSCLC patients and correlated with clinical outcomes, as a single-center retrospective study. TILs and programmed death ligand-1 (PD-L1) were assessed on biopsies (N = 93) or surgical resections (N = 14) before first-line pembrolizumab. Results A low number of stromal CD4 TILs were significantly associated with bone metastasis and poor performance status (PS). The median progression-free survival (PFS) and overall survival (OS) were significantly higher in patients with a high number of stromal CD4 TILs (336 days and 731 days, respectively) than in those with low infiltration (204 days and 333 days, respectively). Patients with a high number of intratumoral CD8 TILs (731 days) yielded significantly better OS than those with low infiltration (333 days), but not for PFS. Multivariate analysis confirmed that stromal CD4 TILs were independent predictors of PFS, but not OS. Furthermore, intratumoral CD8 TILs were independent predictors of better OS. In the survival analysis of key subgroups, stromal CD4 TILs were identified as significant predictors of survival in patients with non-adenocarcinomatous histology and PD-L1 ≥ 50%. Conclusion Stromal CD4 TILs were identified as a significant marker for predicting the PFS after pembrolizumab therapy, especially in patients with non-adenocarcinoma and high PD-L1 expression. In addition, intratumoral CD8 TILs were identified as significant predictors of OS.

Extended ICI treatment after first‐line chemoimmunotherapy could predict the clinical benefit of ramucirumab plus docetaxel in advanced non‐small lung cancer: Post hoc analysis from NEJ051 (REACTIVE study)

“…In general, ICIs promote the entry of CD4, CD8, and other tumor‐infiltrating lymphocytes (TILs) into tumors, where they subsequently kill tumor cells 19 . Angiogenetic proteins such as vascular endothelial growth factor (VEGF) and VEGFR create an immunosuppressive tumor microenvironment, with resultant increases in the expression of FOXP3 and the number of myeloid‐derived suppressor cells 20–22 .…”

“…In general, ICIs promote the entry of CD4, CD8, and other tumor‐infiltrating lymphocytes (TILs) into tumors, where they subsequently kill tumor cells. 19 Angiogenetic proteins such as vascular endothelial growth factor (VEGF) and VEGFR create an immunosuppressive tumor microenvironment, with resultant increases in the expression of FOXP3 and the number of myeloid‐derived suppressor cells. 20 , 21 , 22 We hypothesize that extended ICI treatment achieves a tumor microenvironment in which CD4/CD8 TIL levels are high and FOXP3 levels are low, contributing to the downregulation of VEGF signaling.…”

Progresses in biomarkers for cancer immunotherapy

“…Moreover, another multicenter cohort study in dMMR mCRC patients illustrates that low levels of peripheral CD4+T cells and CD4+/CD8+ ratio could be positive independent potential biomarkers for predicting survival outcomes, 117 further supporting the critical role of CD4+T cells in promoting CD8+ T cells antitumor activities. And by a recent clinicopathological study indicated CD4 in the stroma was consistently associated with PD‐L1 in 50% of the patients; however, the CD8 in intratumoral lesions was associated with PD‐L1 in 1−49% 118 . Despite this, it is unclear if CD4+ T cells with PD‐L1 expression correlate with prognosis after first‐line anti‐PD‐1 treatment.…”

Patient-derived tumoroids and proteomic signatures: tools for early drug discovery

“…However, PBMCs are less predictive compared to tumor-infiltrated immune cells. As tumor-infiltrated immune cells are in contact with tumoral cells, a predictive value of these cells has been assigned to immunotherapy responses ( 13 ). For example, for non-responders to immunotherapy, an increased proportion of myeloid-derived suppressor cells (MDSCs), and a decreased proportion of natural killer (NK) cells, and monocytes in the tumor site constitute an immunosuppressive microenvironment.…”