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Tumor-Intrinsic SIRPA Promotes Sensitivity to
Abstract:
Checkpoint inhibition immunotherapy has revolutionized cancer treatment, but many patients show resistance. 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 system. Mice bearing SIRPA-deficient melanoma tumors show no response to anti-PD-L1 treatment, whereas melanoma-specific SIRPA overexpression significantly enhances immunotherapy response. Mechanistically, 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.
Abstract:
Checkpoint inhibition immunotherapy has revolutionized cancer treatment, but many patients show resistance. 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 system. Mice bearing SIRPA-deficient melanoma tumors show no response to anti-PD-L1 treatment, whereas melanoma-specific SIRPA overexpression significantly enhances immunotherapy response. Mechanistically, 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.
The big questions
The big questions
The functional status of which immuno-oncology targets/checkpoints can help predict therapeutic responses to well-established ICIs?
Are these effects context-dependent? If so, to what extent?
Major discoveries
Major discoveries
SIRP⍺, thought to be an inhibitory immune checkpoint exclusively expressed on myeloid cells, is also present in melanoma cells and mediates T-cell-killing through the interaction with CD47, thus promoting sensitivity to anti-PD-1.
SIRP⍺ is a robust marker for melanocytic lineage differentiation and is partially regulated by its pseudogene counterpart, SIRPAP1.
My contributions
My contributions
Co-leading in conceptualization
Leading in formal analysis of public single-cell RNA-seq, spatial transcriptomics, and differentiation-related bulk RNA-seq data
Substantially contributed to manuscript writing
Future directions
Future directions
Further mechanistic investigation into the molecular signaling that mediates SIRPA-CD47 interaction between melanoma cells and CD8+ T cells and how it differentiates from that in macrophages
Development of macrophage-specific anti-SIRPA antibodies using a bi-specific construct
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