Predictive Markers for Anti-PD-1/PD-L1 Therapy in Non-Small Cell Lung Cancer

Where Are We?

Matthew Evans; Brendan O'Sullivan; Matthew Smith; Philippe Taniere


Transl Lung Cancer Res. 2018;7(6):682-690. 

In This Article

CD8 T-cells

In order for the immune system to recognise a malignant cell, it is necessary that the cell has high TMB (and so expresses a sufficient number of neoantigens) and that it expresses checkpoint inhibitors at a low level. However, these two factors are immaterial if there is no immune system presence to drive the anti-tumour immune response. In the case of anti-tumour activity, the key actor in the immune response is the CD8-positive cytotoxic T-cells.

The early evidence for the prognostic and predictive role of CD8 T-cells derives from melanoma, in which there is evidence that high densities of tumour-infiltrating lymphocytes are associated with improved prognosis[28] and that this may also have predictive value in the context of immunotherapy.[29]

As in melanoma, there is evidence that CD8 T-cell density is a prognostic marker in NSCLC. There is now reasonable evidence that increased density of tumour-associated CD8-positive T-cells is associated with improved prognosis in NSCLC.[30–33] To date, however, there is no compelling evidence to suggest that increased numbers of tumour-infiltrating CD8 T-cells are associated with improved response to checkpoint inhibitors. A very recently-published study, however, has demonstrated that increased numbers of peripheral blood CD8 T-cells after administration of pembrolizumab is associated with improved treatment response in NSCLC.[34] While this certainly does not prove a predictive role for intratumoral T-cells, it certainly makes it plausible.

The extent to which CD8 T-cell infiltration assessment will become routine in clinical practice is unclear; it is certainly fair to say that the underlying evidence has lagged substantially behind that of PD-L1 expression and TMB. In part, this may relate to methodological difficulties in clinically validating the prognostic and predictive implications of CD8 T-cell infiltration. Much like PD-L1, it is probable that such infiltrates demonstrate substantial spatial and temporal heterogeneity, which would make determination of anything other than large prognostic/predictive impacts difficult to establish.