Cancer Evolution during Immunotherapy

Abstract

Immune checkpoint blockade has revolutionized cancer treatment. In this issue of Cell, insights from a longitudinal multi-omics analysis of the largest yet-reported cohort of melanoma patients reveal how tumor and immunity co-evolve during anti-PD-1 therapy.

Figure 1

Parallel analysis of tumor mutational composition, and TCR sequencing demonstrates a delicate interplay of tumor cell mutational contraction, subclonal evolution, and T cell repertoire sculpting in keeping with concepts of immuno-editing and immune checkpoint molecule action. In tumors which fail to respond to anti-PD-1 therapy (TOP), tumors (at left) may show persistence of major clones, expansion of sub-clones, adaptive loss of neoantigen expression on some or all cells of previously-expressing clones, and emergence of new subclones. The corresponding T cell repertoire (at right) may show failure to recruit/expand tumor-specific T cell clones, and upregulation of inhibitory checkpoint molecule expression, resulting in incomplete elimination of tumor (sub)clones. In tumors that respond to anti-PD-1 therapy (BOTTOM, at left), subclonal tumor cell elimination - most characteristically of mutational subclones which uniformly express and present immunogenic mutational products - is accompanied by overall mutational contraction. However, major clones and neoantigen non-expressing tumor cells may persist. Corresponding T cell repertoires (at right) may demonstrate release from inhibitory checkpoints and expansion of (pre-existing) tumor-specific T cell clones, relative loss of tumor non-specific or ineffective T cell clones, and an associated decrease in TCR diversity measures.