Faculty, Staff and Student Publications
Publication Date
11-14-2022
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.
Keywords
Animals, Mice, B7-H1 Antigen, CD8-Positive T-Lymphocytes, Ecosystem, Immunotherapy, Melanoma, Proteomics, Humans
DOI
10.1016/j.ccell.2022.10.012
PMID
36332624
PMCID
PMC9669221
PubMedCentral® Posted Date
11-14-2023
PubMedCentral® Full Text Version
Author MSS
Graphical Abstract
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Dermatology Commons, Immunotherapy Commons, Medical Sciences Commons, Oncology Commons, Skin and Connective Tissue Diseases Commons
