Nicole Baldwin Ph.D.

Banchereau, R., Leng, N., Zill, O., Sokol, E., Liu, G., Pavlick, D., Maund, S., Liu, L.F., Kadel, E., 3rd, Baldwin, N., Jhunjhunwala, S., Nickles, D., Assaf, Z.J., Bower, D., Patil, N., McCleland, M., Shames, D., Molinero, L., Huseni, M., Sanjabi, S., Cummings, C., Mellman, I., Mariathasan, S., Hegde, P. and Powles, T. (2021). “Molecular determinants of response to PD-L1 blockade across tumor types.” Nat Commun 12(1): 3969.

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Immune checkpoint inhibitors targeting the PD-1/PD-L1 axis lead to durable clinical responses in subsets of cancer patients across multiple indications, including non-small cell lung cancer (NSCLC), urothelial carcinoma (UC) and renal cell carcinoma (RCC). Herein, we complement PD-L1 immunohistochemistry (IHC) and tumor mutation burden (TMB) with RNA-seq in 366 patients to identify unifying and indication-specific molecular profiles that can predict response to checkpoint blockade across these tumor types. Multiple machine learning approaches failed to identify a baseline transcriptional signature highly predictive of response across these indications. Signatures described previously for immune checkpoint inhibitors also failed to validate. At the pathway level, significant heterogeneity is observed between indications, in particular within the PD-L1(+) tumors. mUC and NSCLC are molecularly aligned, with cell cycle and DNA damage repair genes associated with response in PD-L1- tumors. At the gene level, the CDK4/6 inhibitor CDKN2A is identified as a significant transcriptional correlate of response, highlighting the association of non-immune pathways to the outcome of checkpoint blockade. This cross-indication analysis reveals molecular heterogeneity between mUC, NSCLC and RCC tumors, suggesting that indication-specific molecular approaches should be prioritized to formulate treatment strategies.

Rinchai, D., B. Syed Ahamed Kabeer, M. Toufiq, Z. Tatari-Calderone, S. Deola, T. Brummaier, M. Garand, R. Branco, N. Baldwin, M. Alfaki, M. C. Altman, A. Ballestrero, M. Bassetti, G. Zoppoli, A. De Maria, B. Tang, D. Bedognetti and D. Chaussabel (2020). “A modular framework for the development of targeted Covid-19 blood transcript profiling panels.” J Transl Med 18(1): 291.

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BACKGROUND: Covid-19 morbidity and mortality are associated with a dysregulated immune response. Tools are needed to enhance existing immune profiling capabilities in affected patients. Here we aimed to develop an approach to support the design of targeted blood transcriptome panels for profiling the immune response to SARS-CoV-2 infection. METHODS: We designed a pool of candidates based on a pre-existing and well-characterized repertoire of blood transcriptional modules. Available Covid-19 blood transcriptome data was also used to guide this process. Further selection steps relied on expert curation. Additionally, we developed several custom web applications to support the evaluation of candidates. RESULTS: As a proof of principle, we designed three targeted blood transcript panels, each with a different translational connotation: immunological relevance, therapeutic development relevance and SARS biology relevance. CONCLUSION: Altogether the work presented here may contribute to the future expansion of immune profiling capabilities via targeted profiling of blood transcript abundance in Covid-19 patients.

Singhania, A., C. M. Graham . . . N. Baldwin, D. Chaussabel, V. Papayannopoulos, A. Wack, J. F. Banchereau, V. M. Pascual and A. O’Garra (2019). “Transcriptional profiling unveils type I and II interferon networks in blood and tissues across diseases.” Nat Commun 10(1): 2887.

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Understanding how immune challenges elicit different responses is critical for diagnosing and deciphering immune regulation. Using a modular strategy to interpret the complex transcriptional host response in mouse models of infection and inflammation, we show a breadth of immune responses in the lung. Lung immune signatures are dominated by either IFN-gamma and IFN-inducible, IL-17-induced neutrophil- or allergy-associated gene expression. Type I IFN and IFN-gamma-inducible, but not IL-17- or allergy-associated signatures, are preserved in the blood. While IL-17-associated genes identified in lung are detected in blood, the allergy signature is only detectable in blood CD4(+) effector cells. Type I IFN-inducible genes are abrogated in the absence of IFN-gamma signaling and decrease in the absence of IFNAR signaling, both independently contributing to the regulation of granulocyte responses and pathology during Toxoplasma gondii infection. Our framework provides an ideal tool for comparative analyses of transcriptional signatures contributing to protection or pathogenesis in disease.

Blazkova, J., S. Gupta, Y. Liu, B. Gaudilliere, E. A. Ganio, C. R. Bolen, R. Saar-Dover, G. K. Fragiadakis, M. S. Angst, S. Hasni, N. Aghaeepour, D. Stevenson, N. Baldwin, E. Anguiano, D. Chaussabel, M. C. Altman, M. J. Kaplan, M. M. Davis and D. Furman (2017). “Multicenter systems analysis of human blood reveals immature neutrophils in males and during pregnancy.” J Immunol 198(6): 2479-2488.

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Despite clear differences in immune system responses and in the prevalence of autoimmune diseases between males and females, there is little understanding of the processes involved. In this study, we identified a gene signature of immature-like neutrophils, characterized by the overexpression of genes encoding for several granule-containing proteins, which was found at higher levels (up to 3-fold) in young (20-30 y old) but not older (60 to >89 y old) males compared with females. Functional and phenotypic characterization of peripheral blood neutrophils revealed more mature and responsive neutrophils in young females, which also exhibited an elevated capacity in neutrophil extracellular trap formation at baseline and upon microbial or sterile autoimmune stimuli. The expression levels of the immature-like neutrophil signature increased linearly with pregnancy, an immune state of increased susceptibility to certain infections. Using mass cytometry, we also find increased frequencies of immature forms of neutrophils in the blood of women during late pregnancy. Thus, our findings show novel sex differences in innate immunity and identify a common neutrophil signature in males and in pregnant women.

Blazkova, J., S. Gupta, Y. Liu, B. Gaudilliere, E. A. Ganio, C. R. Bolen, R. Saar-Dover, G. K. Fragiadakis, M. S. Angst, S. Hasni, N. Aghaeepour, D. Stevenson, N. Baldwin, E. Anguiano, D. Chaussabel, M. C. Altman, M. J. Kaplan, M. M. Davis and D. Furman (2017). “Multicenter systems analysis of human blood reveals immature neutrophils in males and during pregnancy.” J Immunol 198(6): 2479-2488.

Full text of this article.

Despite clear differences in immune system responses and in the prevalence of autoimmune diseases between males and females, there is little understanding of the processes involved…Using mass cytometry, we find increased frequencies of immature forms of neutrophils in the blood of women during late pregnancy. Thus, our findings show novel sex differences in innate immunity and identify a common neutrophil signature in males and in pregnant women.