Hubei Cancer Hospital

Our previous studies showed HMGB3 expression may correlate with immunotherapy efficacy in breast cancer patients. Here, we investigated whether HMGB3 overexpression has an impact on anti‐PD‐1 therapy in triple‐negative breast cancer (TNBC) and its molecular mechanisms. Animal models were established to observe the effect of HMGB3 on sensitivity to anti‐PD‐1 treatment. Correlation of HMGB3 expression and ferroptosis preventive proteins in TNBC patients' tissues with anti‐PD‐1 therapy efficacy was analyzed. The impact of HMGB3 on IFN‐γ (Interferon‐gamma) inhibitory effects and signaling was examined in human TNBC cells where HMGB3 expression was knocked down using siRNA. Moreover, TNBC cells stably transfected with lentiviral vectors containing cDNA of HMGB3 were also used to confirm the effect of overexpression of HMGB3 on IFN‐γ inhibitory effect and signaling. Effect of HMGB3 on IFN‐γ‐driven ferroptosis and ferroptosis‐associated protein expression were also investigated. Correlation of HMGB3 and IRF1 and GPX4 expression in patient's cancer tissue were also investigated. Our results demonstrated that HMGB3 expression contributes to resistance to anti‐PD‐1 therapy in vivo. HMGB3 expression correlated with treatment efficacy of immunotherapy and survival in TNBC patients. HMGB3 silence decreased resistance of breast cancer cells to IFN‐γ cytotoxic effect, while HMGB3 overexpression increased resistance of these cancer cells. HMGB3 silence increased STAT1 phosphorylation and IRF1 expression upon IFN‐γ treatment compared with control. Overexpression of HMGB3 inhibited STAT1 phosphorylation and IFN‐γ signaling in TNBC cells. Moreover, HMGB3 also increased STAT3 activation and had an effect of interaction between STAT1 and STAT3. HMGB3 overexpression decreased IFN‐γ‐driven ferroptosis in TNBC cells. HMGB3 increased ferroptosis‐inhibitory proteins (SLC7A11, GPX4, and SLC3A2) expression in TNBC cells. Ferroptosis inhibition recovers resistance to anti‐PD‐1 therapy in vivo. Immunohistochemistry showed HMGB3 expression correlated with ferroptosis‐associated proteins and IRF1 expression in breast cancer tissue. HMGB3 contributes to anti‐PD‐1 resistance by inhibiting IFN‐γ‐driven ferroptosis in TNBC which suggested HMGB3 is a potential co‐target with anti‐PD‐1 therapy for TNBC.

Prolgolimab is an IgG1 anti-PD-1 monoclonal antibody with the Fc-silencing 'LALA' mutation. The phase III DOMAJOR study assessed efficacy and safety of prolgolimab in combination with pemetrexed and platinum-based chemotherapy vs placebo in combination with pemetrexed and platinum-based chemotherapy as first-line treatment for advanced non-small cell lung cancer (NSCLC).

292 patients with advanced non-squamous NSCLC were randomized 1:1 to receive 4 cycles of pemetrexed, platinum-based drug and either prolgolimab (3 mg/kg Q3W) or placebo followed by prolgolimab/placebo with pemetrexed until disease progression or toxicity (≤36 months). The primary endpoint was overall survival (OS).

After a median follow-up of 18 months, the median OS was not reached (95 % CI, 22.28 - NA) in the prolgolimab-combination group vs 14.6 months (95 % CI, 11.73 - 19.15) in the placebo-combination group (HR, 0.51; 95 % CI, 0.35 - 0.73, p = 0.0001). The OS improvement was independent of PD-L1 status. Median progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) was 7.7 months in the prolgolimab-combination group and 5.5 months in the placebo-combination group (HR, 0.65; 95 % CI, 0.49 - 0.85, p = 0.0004). The only adverse events that were reported in at least 10 % of the patients that were significantly more frequent in the prolgolimab-combination group were blood creatinine increased and dyspnoea.

Among patients with advanced NSCLC the addition of prolgolimab to pemetrexed and a platinum-based drug increased OS and PFS, with no new safety concerns. This benefit was retained in patients with PD-L1 negative tumors. (ClinicalTrials.gov, NCT03912389).