Program Official

Principal Investigator

Jia-Ren
Lin
Awardee Organization

Harvard Medical School
United States

Fiscal Year
2023
Activity Code
R50
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Advancing technologies for the collection and analysis of high dimensional immunoprofiles and tumor images

-ABSTRACT The overall goal of this proposal is to use highly multiplexed, high-resolution imaging of tissues and tumors to deeply characterize the microenvironments of diverse solid tumors being studied by NCI-funded collaborators at the Harvard Laboratory of Systems Pharmacology (LSP), Dana Farber/Harvard Cancer Center and four other NCI cancer centers. The PI of this proposal, Research Specialist Jerry Lin PhD, invented tissue-based cyclic immunofluorescence (CyCIF) in 2018 and has made it the leading public domain (license-free) method for performing high-plex tissue analysis. He has adapted the method to high resolution 3D imaging of selected fields of view (~103 cells using deconvolution microscopy) as well as rapid analysis of whole slides (~106 cells) at lower resolution. As developed CyCIF can collect data from 20-60 protein markers from a single specimen making it possible to identify cell types and states in a preserved tissue environment. It can also image structures as small as immune synapses allowing cell-cell interactions to be analyzed at a functional level. Dr. Lin’s work directly supports research by 18 NCI-funded laboratories and the CyCIF protocols he has published are used by multiple other labs working independent of the HMS team. Dr. Lin also performs his own research as part of a Human Tumor Atlas Network Trans Network Project that conceived and now leads. These activities have resulted in 20 collaborative publications over the past three years including several in high impact journals with Dr. Lin as first or co-first author. As part of this R50 proposal Dr Lin will engage in three primary activities. First, he will continue to collaborate with research groups to acquire CyCIF data at different stages before and after treatment. This is will make it possible to identify molecular and morphological features associated with disease initiation, progression, and therapeutic response. Second, he will continue to improve the CyCIF method and integrate it with other methods for spatial interrogation of human and murine tumors (e.g. transcript profiling and imaging mass spectrometry). Dr. Lin will also continue to lead an HTAN TNP designed to compare spatial profiling methods across technologies and performance sites. This research has already led to unexpected insights into adequately powering spatial profiles as well as the relative merits of whole-slide 2D and 3D imaging. Third, he will continue to develop and validate new approaches to tissue imaging, particularly those that are applicable to digital pathology workflows in the setting of clinical trials and patient diagnosis. This builds on the proven ability of CyCIF to collect high quality data from the formaldehyde-fixed paraffin embedded (FFPE) specimens routinely acquired for patient diagnosis and staging (including core biopsies and fine needle aspirates). This combination of collaborative and original research and technology development is expected to have a high impact on an emerging area of translational cancer biology and is fully consistent with the roles expected of a laboratory-based R50 Research Specialist.

Publications

  • Lin JR, Wang S, Coy S, Chen YA, Yapp C, Tyler M, Nariya MK, Heiser CN, Lau KS, Santagata S, Sorger PK. Multiplexed 3D atlas of state transitions and immune interaction in colorectal cancer. Cell. 2023 Jan 19;186(2):363-381.e19. PMID: 36669472
  • Gaglia G, Burger ML, Ritch CC, Rammos D, Dai Y, Crossland GE, Tavana SZ, Warchol S, Jaeger AM, Naranjo S, Coy S, Nirmal AJ, Krueger R, Lin JR, Pfister H, Sorger PK, Jacks T, Santagata S. Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma. Cancer cell. 2023 May 8;41(5):871-886.e10. Epub 2023 Apr 13. PMID: 37059105
  • Notarangelo G, Spinelli JB, Perez EM, Baker GJ, Kurmi K, Elia I, Stopka SA, Baquer G, Lin JR, Golby AJ, Joshi S, Baron HF, Drijvers JM, Georgiev P, Ringel AE, Zaganjor E, McBrayer SK, Sorger PK, Sharpe AH, Wucherpfennig KW, Santagata S, Agar NYR, Suvà ML, Haigis MC. Oncometabolite d-2HG alters T cell metabolism to impair CD8+ T cell function. Science (New York, N.Y.). 2022 Sep 30;377(6614):1519-1529. Epub 2022 Sep 29. PMID: 36173860
  • Guerriero JL, Lin JR, Pastorello RG, Du Z, Chen YA, Townsend MG, Shimada K, Hughes ME, Ren S, Tayob N, Zheng K, Mei S, Patterson A, Taneja KL, Metzger O, Tolaney SM, Lin NU, Dillon DA, Schnitt SJ, Sorger PK, Mittendorf EA, Santagata S. Qualification of a multiplexed tissue imaging assay and detection of novel patterns of HER2 heterogeneity in breast cancer. NPJ breast cancer. 2024 Jan 2;10(1):2. PMID: 38167908
  • Ternes L, Lin JR, Chen YA, Gray JW, Chang YH. Computational multiplex panel reduction to maximize information retention in breast cancer tissue microarrays. PLoS computational biology. 2022 Sep 30;18(9):e1010505. doi: 10.1371/journal.pcbi.1010505. eCollection 2022 Sep. PMID: 36178966
  • Lin JR, Chen YA, Campton D, Cooper J, Coy S, Yapp C, Tefft JB, McCarty E, Ligon KL, Rodig SJ, Reese S, George T, Santagata S, Sorger PK. High-plex immunofluorescence imaging and traditional histology of the same tissue section for discovering image-based biomarkers. Nature cancer. 2023 Jul;4(7):1036-1052. Epub 2023 Jun 22. PMID: 37349501