Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1–targeted therapy in lung cancer patients

Abstract

Exhausted T cells in chronic infections and cancer have sustained expression of the inhibitory receptor programmed cell death 1 (PD-1). Therapies that block the PD-1 pathway have shown promising clinical results in a significant number of advanced-stage cancer patients. Nonetheless, a better understanding of the immunological responses induced by PD-1 blockade in cancer patients is lacking. Identification of predictive biomarkers is a priority in the field, but whether peripheral blood analysis can provide biomarkers to monitor or predict patients’ responses to treatment remains to be resolved. In this study, we analyzed longitudinal blood samples from advanced stage non–small cell lung cancer (NSCLC) patients (n = 29) receiving PD-1–targeted therapies. We detected an increase in Ki-67+ PD-1+ CD8 T cells following therapy in ∼70% of patients, and most responses were induced after the first or second treatment cycle. This T-cell activation was not indiscriminate because we observed only minimal effects on EBV-specific CD8 T cells, suggesting that responding cells may be tumor specific. These proliferating CD8 T cells had an effector-like phenotype (HLA-DR+, CD38+, Bcl-2lo), expressed costimulatory molecules (CD28, CD27, ICOS), and had high levels of PD-1 and coexpression of CTLA-4. We found that 70% of patients with disease progression had either a delayed or absent PD-1+ CD8 T-cell response, whereas 80% of patients with clinical benefit exhibited PD-1+ CD8 T-cell responses within 4 wk of treatment initiation. Our results suggest that peripheral blood analysis may provide valuable insights into NSCLC patients’ responses to PD-1–targeted therapies.

Distinct Cellular Mechanisms Underlie Anti-CTLA-4 and Anti-PD-1 Checkpoint Blockade

“…For example, the necessity and sufficiency of specific ICB responsive tumor infiltrating T cell subsets identified in our study remains to be definitively tested. Furthermore, recent studies have shown that anti-PD-1 therapy leads to a dynamic expansion of proliferating PD-1 + CD8 T cells in peripheral blood of melanoma and lung cancer patients(Huang et al, 2017; Kamphorst et al, 2017). Whether expansion of ICB responsive exhausted-like CD8 T cells is driven by therapeutic engagement of peripheral or tumor infiltrating populations is unknown.…”

Predictive factors of response to immunotherapy—a review from the Spanish Melanoma Group (GEM)

“…Recently, an interesting report demonstrated that the increase of CD8+ T cells PD1 positive in peripheral blood after 4 weeks of starting the anti PD-1 antibody therapy correlates with clinical benefit in lung cancer patients (28). In melanoma, there are data indicating an increase of CD8 memory T cells into the tumor, and a possible increase in peripheral blood of a subset of dendritic cells, or HLA-DR NK cells, in patients with a response to therapy after anti PD-1 treatment (29).…”

Immune checkpoint blockade in infectious diseases

“…There are also more complex “gene signatures” in tumours to identify patients who will show the best responses 6 . Earlier T cell expansion following anti-PD-1 therapy in small lung cancer has been associated with improved responses 7 and a composite biomarker of the T cell proliferative response together with pre-treatment tumor burden can predict response to anti-PD-1 in individuals with metastatic melanoma 8 . Given the cost and toxicity of immune checkpoint blockade, identifying biomarkers that predict a clinical response are currently a top priority.…”