TGFβ Is a Master Regulator of Radiation Therapy-Induced Antitumor Immunity

Abstract

T cells directed to endogenous tumor antigens are powerful mediators of tumor regression. Recent immunotherapy advances have identified effective interventions to unleash tumor-specific T cell activity in patients who naturally develop them. Eliciting T cell responses to a patient's individual tumor remains a major challenge. Radiation therapy can induce immune responses to model antigens expressed by tumors, but it remains unclear if it can effectively prime T cells specific for endogenous antigens expressed by poorly immunogenic tumors. We hypothesized that TGFβ activity is a major obstacle hindering the ability of radiation to generate an in situ tumor vaccine. Here we show that antibody-mediated TGFβ neutralization during radiation therapy effectively generates CD8+ T cell responses to multiple endogenous tumor antigens in poorly immunogenic mouse carcinomas. Generated T cells were effective at causing regression of irradiated tumors and non-irradiated lung metastases or synchronous tumors (abscopal effect). Gene signatures associated with IFNγ and immune-mediated rejection were detected in tumors treated with radiation therapy and TGFβ blockade in combination but not as single agents. Upregulation of programmed death (PD) ligand-1 and -2 in neoplastic and myeloid cells and PD-1 on intratumoral T cells limited tumor rejection resulting in rapid recurrence. Addition of anti-PD-1 antibodies extended survival achieved with radiation and TGFβ blockade. Thus, TGFβ is a fundamental regulator of radiation therapy ability to generate an in situ tumor vaccine. The combination of local radiation therapy with TGFβ neutralization offers a novel individualized strategy for vaccinating patients against their tumors.

Targeting TGF-β Signaling for Therapeutic Gain

“…LY2109761, which targets the kinase activities of TbRII and TbRI (Sawyer et al 2003;Yingling et al 2004), and the antipan TGF-b antibody, 1D11 (Morris et al 2014), attenuate radiation-induced activation of p53 and ATM in breast cancer cells in culture and in vivo, suggesting that TGF-b signaling may potentiate therapeutic killing of tumors by preventing DNA repair and accentuating the cytotoxic effect of radiation (Bouquet et al 2011). Furthermore, TGF-b blockade with the 1D11 antibody significantly stimulates the anticancer immune response against implanted mammary tumors (4T1 cells) following RT, resulting in tumor clearance when combined with RT (Vanpouille-Box et al 2015). Even short-term dosing with TGF-b inhibitors might provide a considerable therapeutic window in potentiating radiotherapy.…”

“…Moreover, RT can cause disfiguring and painful fibrosis, itself a target for anti-TGF-b therapy, possibly providing an added benefit of TGF-b inhibition (Anscher et al 2008). Thus, TGF-b blockade may have a triad of benefits, stimulating radiationinduced tumor cell killing (Bouquet et al 2011), augmenting immune rejection ( Vanpouille-Box et al 2015), while limiting radiation-induced fibrosis (Rabbani et al 2003;Anscher et al 2008). This approach is part of an active clinical trial of fresolimumab in combination with radiotherapy for metastatic breast cancer (NCT01401062).…”

Radiation therapy and the abscopal effect: a concept comes of age

“…For example, several novel categories of targeted immunomodulators have recently been developed. They include TLR agonists, TGF-β antagonists and the immune checkpoint inhibitors, anti CTLA-4, anti PD-1, and anti PD-L1/L2 agents, which have re-kindled hope for successful cancer immunotherapy (21)(22)(23)(24). There are numerous other potential immunomodulatory agents in the investigational pipeline.…”

Irradiation and immunotherapy: From concept to the clinic

“…The addition of anti-PD-1 therapy subsequently improved survival, highlighting the complexity surrounding the generation of a successful immune-mediated antitumor response. 35 Collectively, these data provide a strong preclinical rationale for exploring the combination of PD-1/PDL-1 blockade with RT. To date, there are no published articles reporting the outcomes of patients who received treatment with PD-1/PDL-1 inhibitors and RT, although many trials are planned or are underway (National Clinical Trials NCT02407171, NCT02303366, and NCT02289209; clinicaltrials.gov).…”