A single cell atlas reveals distinct immune landscapes in transplant and primary tumors that determine response or resistance to immunotherapy

Abstract

Despite impressive responses in some patients, immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Nearly all preclinical immunotherapy studies utilize transplant tumor models, but cure rates of transplant tumor models treated with immunotherapy often overestimate patient responses. Here, we show that transplant tumors are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous tumors. We generated a single-cell atlas of tumor-infiltrating immune cells from transplant and primary tumors treated with radiation and immunotherapy, which reveals striking differences in their immune landscapes. Although radiotherapy remodels myeloid cell phenotypes in primary and transplant tumors, only transplant tumors are enriched for CD8+ T cells that mediate tumor clearance while mice with primary sarcomas demonstrate tumor-specific tolerance. These results identify distinct microenvironments in tumors that coevolve with the immune system, which promote tolerance that must be overcome for immune-mediated cancer cures.

4-1BB is a target for immunotherapy in patients with undifferentiated pleomorphic sarcoma

“…Maximising responses to radiotherapy is likely to require a range of immunotherapy options, from ICIs such as anti-PD-1 to co-stimulatory agonists such as 4-1BB. In the previously mentioned primary versus transplant preclinical model of sarcoma, the immune tolerance observed for primary tumours extended to resistance to radiotherapy and dual checkpoint blockade with PD-1 and CTLA-4 48 . Single-cell sequencing revealed low numbers of activated T cells in primary tumours even after anti-PD-1 treatment.…”

“…It remains to be seen what impact these variables may have on radiotherapy and immunotherapy combinations. Recent preclinical data in sarcoma that used primary vs transplanted tumour indicated basal and post-radiotherapy ISG signatures were similar, yet only transplanted tumours could be cured by radiotherapy plus anti-PD-1 48 . This indicates that overcoming other factors such as immune tolerance may be of greater concern for clinical responses.…”