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D. Gabrilovich



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    MINI 02 - Immunotherapy (ID 92)

    • Event: WCLC 2015
    • Type: Mini Oral
    • Track: Biology, Pathology, and Molecular Testing
    • Presentations: 1
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      MINI02.12 - Distribution of Immune Markers and Their Association with Overall Survival and Time to Progression in Non-Small-Cell Lung Cancer (NSCLC) (ID 3108)

      11:50 - 11:55  |  Author(s): D. Gabrilovich

      • Abstract
      • Presentation
      • Slides

      Background:
      Inducible nitric oxide synthase (iNOS) and reactive nitrosylation are important mediators of tumor immunosuppression by myeloid-derived suppressor cells (MDSCs). However, the role of CD33+ peritumoral PMN-MDSCs in these pathways remains unclear. We conducted a retrospective cohort study of NSCLC subjects treated with surgery, with the primary objective to determine the association of MDSC biomarkers with time to progression (TTP) and overall survival (OS).

      Methods:
      Inclusion criteria: Surgically treated NSCLC of all stages at a single institution between 1996 and 2010. Somatic mutations tested by PCR. Anti-human antibodies optimized for immunohistochemistry. Samples scored by blinded pathologist based on intensity and percentage of peritumoral cells. Peritumoral nitrotyrosine (NT) and iNOS used Allred scoring. Time to progression (TTP) defined as time from resection to progression event or censored at last evaluation. Overall survival (OS) defined as time from resection to death.

      Results:
      Of 458 tumor samples, 366 lung primaries, 38 soft tissue metastases, and 39 brain metastases. Demographics: median age 67 yrs, 54% female, 96% Caucasian. Of 151 tested for somatic mutations, 36% KRASm, 8.6% EGFRm, 25% p53m, respectively. Histology: adenocarcinoma 76%, squamous 10%. Higher % CD3+ tumor infiltrating lymphocytes (TILs) and CD33+ myeloid cells were observed in tumors than normal tissue (p < .0001 and p = .002, respectively). More CD3+ TILs observed in soft tissue metastases than primary lung tumors (p < .0001). No difference in iNOS expression between tumor and normal lung tissue. More CD3+ TIL was observed in p53 mutant tumors (p=.03). iNOS was positively correlated with CD3+ TIL (p < .001) and CD73+ epithelial cells (p <.001), but not CD33+ myeloid cells. NT expression correlated with the absence of CD3+ TIL (p = .02), consistent with its putative immunosuppressive activity. Median TTP: 10.4 months; 320 (69.7%) events. Median OS: 35.4 months; 353 (77.1%) events. Expectedly, presence of CD3+ TIL was associated with favorable OS; HR 0.5 [0.4 – 0.7], p < .0001, and TTP; HR 0.7 [.5 – .9], p =.009. CD33+ myeloid cells were associated with favorable OS; HR 0.6 [0.5-0.8], p = .0002. Presence of peritumoral iNOS trended toward favorable OS; HR 0.81 [0.6-1.0], p = .07. Peritumoral iNOS was not associated with TTP. Figure 1



      Conclusion:
      Increased presence of TILs in p53 mutant tumors has been reported in other cancers, and may be related to somatic mutational load. An inflamed tumor phenotype was associated with improved overall survival. Unexpectedly, iNOS was positively correlated with both CD3+ infiltration and overall survival.

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