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Alfonso Calvo



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    MA06 - PDL1, TMB and DNA Repair (ID 903)

    • Event: WCLC 2018
    • Type: Mini Oral Abstract Session
    • Track: Biology
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 13:30 - 15:00, Room 206 AC
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      MA06.03 - PD-1 and Id-1 Combined Blockade Impacts Tumor Growth and Survival Through PD-L1 Expression and Tumor Infiltration by Immune-Related Cells  (ID 14033)

      13:40 - 13:45  |  Author(s): Alfonso Calvo

      • Abstract
      • Presentation
      • Slides

      Background

      PD-1/PDL-1 inhibitors are approved in advanced non-small cell lung cancer (NSCLC). Long-term survival rates associated to PD-1/PDL-1 blockade have changed treatment paradigm. However, many patients do not benefit from PD-1/PDL-1 blockade. New therapeutic combinations are under investigation. Id1 is involved in proliferation, angiogenesis and immunosuppression. We described Id1 as an independent prognostic factor in NSCLC (Ponz-Sarvise, Clin Cancer Res 2011) and more recently showed Id1’s role in lung cancer metastasis (Castanon, Cancer Letters 2017). Here we test a combined therapeutic strategy targeting PD-1 and Id1 in a murine lung cancer model.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      Three in vivo studies evaluated the impact of Id1 inhibition in tumor cells, tumor microenvironment and in both, on tumor volumes and mice survival. A syngeneic tumor model using C57BL/6 and Id1-/- Id3+/- mice was created by subcutaneous injection of Lewis Lung Carcinoma (3LL) cells and Id1 silenced 3LL (Id1Sh) cells. After injection, mice were treated with an anti-PD-1 (RMP-1-14) monoclonal antibody or PBS. Tumor volumes according to mice strain, Id1 status in tumor cells and treatment were quantified. Mice's survival was calculated in those groups. Tumor CD8+ and CD3+ TILs and CD68+ cells were quantified by specific immunostainings.

      4c3880bb027f159e801041b1021e88e8 Result

      Id1 inhibition in the tumor environment and the injected tumor cells, combined with anti-PD-1 treatment, induced a significant tumor growth impairment (p < 0.0001) and increased survival (p = 0.0051). CD3+ and CD8+ TILs and tumor CD68 + cells were significantly higher in tumors from mice with the combined Id1-PD-1 blockade treated with the anti-PD-1 inhibitor compared to control animals suggesting that tumor increased immune-related cells infiltration exerts the effector phase of the antitumor immune response. Additionally, PD-L1 expression seemed to be higher when Id1 expression was absent in the immune microenvironment (p = 0.04). Additional data based on multiplexed immunohistochemistry results will be presented at the meeting.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Id1 and PD-1 combined blockade in our syngeneic murine lung cancer model significantly impaired tumor growth and increased survival. Increased tumor PD-L1 expression and CD3+ and CD8+ TILs and CD68+ cells may explain these findings.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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    P1.03 - Biology (Not CME Accredited Session) (ID 935)

    • Event: WCLC 2018
    • Type: Poster Viewing in the Exhibit Hall
    • Track:
    • Presentations: 1
    • Moderators:
    • Coordinates: 9/24/2018, 16:45 - 18:00, Exhibit Hall
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      P1.03-24 - TMPRSS4: A Novel Prognostic Biomarker and Therapeutic Target in NSCLC (ID 11988)

      16:45 - 18:00  |  Author(s): Alfonso Calvo

      • Abstract
      • Slides

      Background

      Genomic analyses are identifying novel genes involved in the pathogenesis of non-small cell lung cancer (NSCLC). TMPRSS4, a membrane-anchored serine protease, was previously found as highly overexpressed in NSCLC. Since proteases have been functionally related to cancer growth and metastasis, we sought to study the prognostic value and role of TMPRSS4 in NSCLC.

      a9ded1e5ce5d75814730bb4caaf49419 Method

      TMPRSS4 expression was evaluated by immunohistochemistry and H-score calculation in TMAs containing a total number of 455 cases. Kaplan-Meier, log-rank and Cox analyses were used to study the prognostic value. In addition, functional assays using NSCLC cell lines and in vivo models were used to assess the possible role of this protease in NSCLC.

      4c3880bb027f159e801041b1021e88e8 Result

      High expression of TMPRSS4 was associated with reduced relapse-free survival (RFS, p=0.003) and overall survival (OS, p=0.007) in NSCLC patients. The prognostic value was also found in patients with stages I-II. Multivariant Cox regression analysis identified TMPRSS4 as an independent prognostic factor in NSCLC for both RFS (HR 1.61 [1.16-2.23], p<0.004) and OS (HR 1.52 [1.14-2.03], p<0.005). In functional studies we developed genetic systems to overexpress or reduce TMPRSS4 levels in lung cancer cells lines. Overexpression in LKR13 cells led to increased clonogenicity, migration and multiorganic metastasis in liver, bone and suprarenal gland. Abrogation of TMPRSS4 in H358 and H2170 cell lines caused a very strong reduction in proliferation (>70%, 96h after plating), clonocenicity (>90%, after 15 days in culture) and subcutaneous tumor growth. Reduction in S and G2/M phases of the cell cycle, increased apoptosis, and changes in gene expression of cell replication- and migration-promoting genes (i.e. MCM6, TYMS and CDKN1A(p21)) were also found. Cells lacking TMPRSS4 were highly sensitized to chemotherapy, including cisplatin, paclitaxel and gemcitabine, which significantly enhanced the antiproliferative, antitumor and proapoptotic effect of these drugs.

      8eea62084ca7e541d918e823422bd82e Conclusion

      Our results show that TMPRSS4 is a biomarker of poor prognosis in NSCLC and plays an important role in tumor growth and metastasis, and suggest that its blockade may enhance sensitivity to chemotherapy.

      6f8b794f3246b0c1e1780bb4d4d5dc53

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