TY - JOUR
T1 - Machine learning links T-cell function and spatial localization to neoadjuvant immunotherapy and clinical outcome in pancreatic cancer
AU - Blise, Katie E.
AU - Sivagnanam, Shamilene
AU - Betts, Courtney B.
AU - Betre, Konjit
AU - Kirchberger, Nell
AU - Tate, Benjamin J.
AU - Furth, Emma E.
AU - Costa, Andressa Dias
AU - Nowak, Jonathan A.
AU - Wolpin, Brian M.
AU - Vonderheide, Robert H.
AU - Goecks, Jeremy
AU - Coussens, Lisa M.
AU - Byrne, Katelyn T.
N1 - Publisher Copyright:
© 2024 American Association for Cancer Research Inc.. All rights reserved.
PY - 2024/5/1
Y1 - 2024/5/1
N2 - Tumor molecular datasets are becoming increasingly complex, making it nearly impossible for humans alone to effectively analyze them. Here, we demonstrate the power of using machine learning (ML) to analyze a single-cell, spatial, and highly multiplexed proteomic dataset from human pancreatic cancer and reveal underlying biological mechanisms that may contribute to clinical outcome. We designed a multiplex immunohistochemistry antibody panel to compare T-cell functionality and spatial localization in resected tumors from treatment-naive patients with localized pancreatic ductal adenocarcinoma (PDAC) with resected tumors from a second cohort of patients treated with neoadjuvant agonistic CD40 (anti-CD40) monoclonal antibody therapy. In total, nearly 2.5 million cells from 306 tissue regions collected from 29 patients across both cohorts were assayed, and over 1,000 tumor microenvironment (TME) features were quantified. We then trained ML models to accurately predict anti-CD40 treatment status and disease-free survival (DFS) following anti-CD40 therapy based upon TME features. Through downstream interpretation of the ML models’ predictions, we found anti-CD40 therapy reduced canonical aspects of T-cell exhaustion within the TME, as compared to treatment-naive TMEs. Using automated clustering approaches, we found improved DFS following anti-CD40 therapy correlated with an increased presence of CD44+CD4+ Th1 cells located specifically within cellular neighborhoods characterized by increased T-cell proliferation, antigen-experience, and cytotoxicity in immune aggregates. Overall, our results demonstrate the utility of ML in molecular cancer immunology applications, highlight the impact of anti-CD40 therapy on T cells within the TME, and identify potential candidate biomarkers of DFS for anti-CD40–treated patients with PDAC.
AB - Tumor molecular datasets are becoming increasingly complex, making it nearly impossible for humans alone to effectively analyze them. Here, we demonstrate the power of using machine learning (ML) to analyze a single-cell, spatial, and highly multiplexed proteomic dataset from human pancreatic cancer and reveal underlying biological mechanisms that may contribute to clinical outcome. We designed a multiplex immunohistochemistry antibody panel to compare T-cell functionality and spatial localization in resected tumors from treatment-naive patients with localized pancreatic ductal adenocarcinoma (PDAC) with resected tumors from a second cohort of patients treated with neoadjuvant agonistic CD40 (anti-CD40) monoclonal antibody therapy. In total, nearly 2.5 million cells from 306 tissue regions collected from 29 patients across both cohorts were assayed, and over 1,000 tumor microenvironment (TME) features were quantified. We then trained ML models to accurately predict anti-CD40 treatment status and disease-free survival (DFS) following anti-CD40 therapy based upon TME features. Through downstream interpretation of the ML models’ predictions, we found anti-CD40 therapy reduced canonical aspects of T-cell exhaustion within the TME, as compared to treatment-naive TMEs. Using automated clustering approaches, we found improved DFS following anti-CD40 therapy correlated with an increased presence of CD44+CD4+ Th1 cells located specifically within cellular neighborhoods characterized by increased T-cell proliferation, antigen-experience, and cytotoxicity in immune aggregates. Overall, our results demonstrate the utility of ML in molecular cancer immunology applications, highlight the impact of anti-CD40 therapy on T cells within the TME, and identify potential candidate biomarkers of DFS for anti-CD40–treated patients with PDAC.
KW - T cell
KW - machine learning
KW - pancreatic ductal adenocarcinoma
KW - spatial proteomics
KW - tumor microenvironment
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U2 - 10.1158/2326-6066.CIR-23-0873
DO - 10.1158/2326-6066.CIR-23-0873
M3 - Article
C2 - 38381401
AN - SCOPUS:85192113246
SN - 2326-6066
VL - 12
SP - 544
EP - 558
JO - Cancer Immunology Research
JF - Cancer Immunology Research
IS - 5
ER -