Lung squamous cell carcinomas (LSCC) pathogenesis remains incompletely understood and biomarkers predicting treatment response remain lacking. Here we describe novel murine LSCC models driven by loss of Trp53 and Keap1, both of which are frequently mutated in human LSCCs. Homozygous inactivation of Keap1 or Trp53 promoted airway basal stem cell (ABSC) self-renewal, suggesting that mutations in these genes lead to expansion of mutant stem cell clones. Deletion of Trp53 and Keap1 in ABSCs, but not more differentiated tracheal cells, produced tumors recapitulating histological and molecular features of human LSCCs, indicating that they represent the likely cell of origin in this model. Deletion of Keap1 promoted tumor aggressiveness, metastasis, and resistance to oxidative stress and radiotherapy (RT). KEAP1/NRF2 mutation status predicted risk of local recurrence after RT in non-small lung cancer (NSCLC) patients and could be non-invasively identified in circulating tumor DNA. Thus, KEAP1/NRF2 mutations could serve as predictive biomarkers for personalization of therapeutic strategies for NSCLCs.

Purpose Local radiation therapy (RT) in combination with systemic anti-CTLA-4 immunotherapy may enhance induction of systemic anti-melanoma immune responses. The primary objective of this trial was to assess the safety and efficacy of combining ipilimumab with RT in patients with stage IV melanoma. Secondary objectives included laboratory assessment of induction of anti-melanoma immune responses. Materials/Methods In our prospective clinical trial, 22 patients with stage IV melanoma were treated with palliative RT and ipilimumab for 4 cycles. RT to 1-2 disease sites was initiated within 5 days after starting ipilimumab. Patients had ≥1 nonirradiated metastasis measuring 7≥1.5 cm for response assessment. Tumor imaging studies were obtained at baseline, 2-4 weeks following cycle 4 of ipilimumab, and every 3 months until progression. Laboratory immune response parameters were measured before and during treatment. Results Combination therapy was well-tolerated without unexpected toxicities. Eleven patients (50.0%) had clinical benefit from therapy, including complete and partial responses (CR, PR) and stable disease (SD) at median follow-up of 55 weeks. Three (27.3%) achieved an ongoing systemic CR at median follow-up of 55 weeks (range 32-65), and 3 (27.3%) had initial PR for a median of 40 weeks. Analysis of immune response data suggests a relationship between elevated CD8-activated T-cells and response. Conclusion This is the second prospective clinical trial of treatment of metastatic melanoma with the combination of RT and systemic immunotherapy and the first using this sequence of therapy. Results from this trial demonstrate that a subset of patients can benefit from combination therapy, arguing for continued clinical investigation into the use of radiation therapy in combination with immunotherapy including PD-1 inhibitors, which may have the potential to be even more effective in combination with radiation.

The use of radiotherapy in combination with targeted immunotherapy as a noninvasive in vivo tumor vaccine strategy appears to be a promising method of enhancing the induction of systemic immune responses and anti-tumor effect.

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