Converging focal radiation and immunotherapy in a preclinical model of triple negative breast cancer: contribution of VISTA blockade

Abstract

Antibodies targeting the co-inhibitory receptor programmed cell death 1 (PDCD1, best known as PD-1) or its main ligand CD274 (best known as PD-L1) have shown some activity in patients with metastatic triple-negative breast cancer (TNBC), especially in a recent Phase III clinical trial combining PD-L1 blockade with taxane-based chemotherapy. Despite these encouraging findings, however, most patients with TNBC fail to derive significant benefits from PD-L1 blockade, calling for the identification of novel therapeutic approaches. Here, we used the 4T1 murine mammary cancer model of metastatic and immune-resistant TNBC to test whether focal radiation therapy (RT), a powerful inducer of immunogenic cell death, in combination with various immunotherapeutic strategies can overcome resistance to immune checkpoint blockade. Our results suggest that focal RT enhances the therapeutic effects of PD-1 blockade against primary 4T1 tumors and their metastases. Similarly, the efficacy of an antibody specific for V-set immunoregulatory receptor (VSIR, another co-inhibitory receptor best known as VISTA) was enhanced by focal RT. Administration of cyclophosphamide plus RT and dual PD-1/VISTA blockade had superior therapeutic effects, which were associated with activation of tumor-infiltrating CD8 + T cells and depletion of intratumoral granulocytic myeloid-derived suppressor cells (MDSCs). Overall, these results demonstrate that RT can sensitize immunorefractory tumors to VISTA or PD-1 blockade, that this effect is enhanced by the addition of cyclophosphamide and suggest that a multipronged immunotherapeutic approach may also be required to increase the incidence of durable responses in patients with TNBC.

VISTA: A Promising Target for Cancer Immunotherapy?

“… Cao et al 58 Samples of TNBC (n=254) Immune cells and tumor cells by IHC VISTA was expressed on immune cells in 87.8% (223/254) of the samples, and on tumor cells in 18.5% (47/254) of the samples. Pilones et al 59 4T1 murine mammary cancer model of metastatic and immune-resistant TNBC NA The efficacy of an antibody specific for VISTA was enhanced by focal RT. Cyclophosphamide + RT and dual PD-1/VISTA blockade had superior therapeutic effects, associated with activation of tumor-infiltrating CD8+ T cells and depletion of intratumoral granulocytic myeloid-derived suppressor cells.…”

“… 58 A further step in the investigation of the therapeutic impact of VISTA in breast cancer was made by Pilones et al, who tested the combination of local radiotherapy and various immunotherapy strategies using a murine mammary cancer model of metastatic and immune-resistant TNBC. 59 They showed that the efficacy of an Ab specific for VISTA was enhanced by local radiotherapy, thus suggesting that a broad immunotherapeutic approach can help to increase durable responses in patients with TNBC. 59 …”

“… 59 They showed that the efficacy of an Ab specific for VISTA was enhanced by local radiotherapy, thus suggesting that a broad immunotherapeutic approach can help to increase durable responses in patients with TNBC. 59 …”

The Role of V-Domain Ig Suppressor of T Cell Activation (VISTA) in Cancer Therapy: Lessons Learned and the Road Ahead

“…Moreover, the combination of inhibitory ICs inhibitors with other cancer therapies might be another appealing strategy to increase the response rates of cancer therapies. Pilones et al have reported that focal radiotherapy and cyclophosphamide can increase the response rates to VISTA inhibitors and PD-1 inhibitors in mice bearing triple-negative breast cancers (84).…”

“…Pilones et al. have reported that focal radiotherapy and cyclophosphamide can increase the response rates to VISTA inhibitors and PD-1 inhibitors in mice bearing triple-negative breast cancers ( 84 ).…”