Therapeutic targeting of inhibitory receptors on T cells can boost immune responses to tumours and improve patient survival but, for reasons that remain unclear, such responses are only seen in a subset of individuals. Studies to identify the processes that govern immunosuppression of tumours have typically been conducted in vitro and have therefore not addressed the complex interaction among tumour cells, immune cells and the tumour microenvironment. Now, a study published in Nature has outlined an approach for the in vivo discovery of immunotherapy targets in melanoma using RNA interference technology, which could pave the way to modification of immune responses in diverse cancer subtypes.

In the current study, Zhou et al. focused on the response of cytotoxic (CD8+) T cells to B16 melanoma, an aggressive tumour, in mice. The researchers constructed two thematic libraries of short hairpin RNA (shRNA) molecules—one targeting genes associated with T cell anergy or exhaustion, the other aimed at genes encoding kinases and phosphatases. CD8+ T cells, each infected with an shRNA from these libraries, were injected into tumour-bearing mice. The T cells were engineered to express the receptor OT-1, and tumour cells expressed the cognate antigen ovalbumin, ensuring homing of the T cells to the tumour target site.