Tumor-intrinsic SIRPA promotes sensitivity to checkpoint inhibition immunotherapy in melanoma

Checkpoint inhibition immunotherapy has revolutionized cancer treatment, but many patients show resis-tance. Here we perform integrative transcriptomic and proteomic analyses on emerging immuno-oncology targets across multiple clinical cohorts of melanoma under anti-PD-1 treatment, on both bulk and single -cell levels. We reveal a surprising role of tumor-intrinsic SIRPA in enhancing antitumor immunity, in contrast to its well-established role as a major inhibitory immune modulator in macrophages. The loss of SIRPA expression is a marker of melanoma dedifferentiation, a key phenotype linked to immunotherapy efficacy. Inhibition of SIRPA in melanoma cells abrogates tumor killing by activated CD8+ T cells in a co-culture sys-tem. Mice bearing SIRPA-deficient melanoma tumors show no response to anti-PD-L1 treatment, whereas melanoma-specific SIRPA overexpression significantly enhances immunotherapy response. Mechanisti-cally, SIRPA is regulated by its pseudogene, SIRPAP1. Our results suggest a complicated role of SIRPA in the tumor ecosystem, highlighting cell-type-dependent antagonistic effects of the same target on immunotherapy.

Automated summary

Checkpoint inhibition immunotherapy has revolutionized cancer treatment, but resistance is still a challenge. This study reveals the role of SIRPA in enhancing antitumor immunity, contrary to its role as an inhibitory immune modulator. The loss of SIRPA expression is linked to melanoma dedifferentiation and reduced efficacy of immunotherapy.