DC-HIL/Gpnmb checkpoint blockade as a synergistic combination for stereotactic ablative radiation (SAbR).

Abstract

e14129 Background: The combination of radiotherapy (RT)/immunotherapy holds a promise as an innovative cancer treatment. Expansion of myeloid-derived suppressor cells (MDSC) dampens cancer immunity, and DC-HIL receptor is a potent mediator of the suppressor function. We examined whether DC-HIL blockade is useful as a synergistic combination for SAbR using mouse model and human clinical samples. Methods: After tumor-irradiation on mice with subcutaneous (sc) RM9 prostate cancer (PC), tumor-infiltrating lymphocytes were phenotypically analyzed. Mice with sc tumor were injected i.v. with RM9-GFP cells (lung mets); 4 d later tumor-irradiated and treated with Ab (6 x 200 μg/shot). Tumor growth was measured by volume or GFP+ cells. PC (n = 22, stages II-III) patients were treated with SAbR, and blood samples collected at week (w) 0, 2, 8 and assayed for % monocytic (m) and granulocytic (g) MDSC and their expression of DC-HIL vs. PDL1. Suppressor function of MDSC was assayed by fall in T cell IFN-γ response. Results: Tumor-RT increased MDSC by 40% on day 8; the most expanded subset Gr1hiLy6Clo gMDSC expressed DC-HIL highly but PDL1 lowly. Combination of anti-DC-HIL/RT inhibited tumor growth in RT-irradiated sc tumor and non-irradiated lung mets and converted tumor microenvironment from the suppressive to the competent milieu. PC patients (17/22 cases) showed elevated MDSC blood levels at w2, but markedly varied at w8 among individuals (2.7 ± 7.3%). DC-HIL+ MDSC levels were also upregulated. gMDSC showed small changes after RT, and DC-HIL (but not PDL1) expression was markedly upgraded by ~90% (n = 3). SAbR decreased the suppressor ability of both MDSC: ~93% T cell suppression at w0 down to ~56% at w8 by mMDSC; and ~76% to ~49% by gMDSC. However, anti-DC-HIL Ab reversed the suppressor ability of MDSC at w8 more than those at w0 (~59% reversal to ~89%), showing that SAbR increased the criticality of DC-HIL pathway in their function. Five cases showed a high rise in DC-HIL expression at w8, with no significant fall in PSA levels at ~13 mons, and one with a noticeable fall in both levels. Conclusions: DC-HIL blockers may amplify the therapeutic effects of SAbR for PC treatment. DC-HIL expression may be a predictive marker for PC response to SAbR.