Acquired resistance to anti-PD1 therapy: checkmate to checkpoint blockade?

Abstract

Anti-programmed cell death 1 (PD1) immunotherapies are among the most effective anti-cancer immunotherapies available; however, a large number of patients present with or develop resistance to them. Unfortunately, very little is known regarding the mechanisms of resistance to such therapies. A recent study sought to identify mutations associated with resistance to anti-PD1 therapy. Results from this study demonstrated that mutations which affected the sensitivity of tumor cells to T-cell-derived interferons, and mutations limiting tumor-cell antigen presentation, could cause acquired resistance. These findings have significant implications for understanding the mechanisms by which anti-PD1 therapies exert their efficacy, comprehending why and how some patients acquire resistance over time, and ultimately guiding the development of combination therapies designed to overcome, or potentially prevent, the development of acquired immunotherapeutic resistance.

Fig. 1

Clonal selection of occult tumor cells harboring T-cell resistance genes. a Tumor at baseline. Circles represent tumor cells and different colors represent intra-tumor heterogeneity with respect to genetic composition. The red tumor cell with a black border harbors T-cell resistance mutations. b Tumor at maximum response. Although the bulk of the tumor is sensitive to immunological assault as a result of anti-PD1 therapy, tumor cells harboring resistance genes are selected for, increasing the ratio of T-cell-resistant to non-resistant cells. c Tumor at progression. The tumor is largely composed of cells containing resistance genes. In the absence of immunological control, metastatic disease is capable of progression and metastasis