Abstract
Neoadjuvant chemotherapy is associated with altered immune cell infiltration and an anti-tumorigenic microenvironment in resected pancreatic cancer
Clinical cancer research
09/21/2022
DOI: 10.1158/1078-0432.CCR-22-1125
PMCID: PMC9999119
PMID: 36129461
Abstract
PURPOSENeoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood. EXPERIMENTAL DESIGNWe employed quantitative, spatially-resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n=299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n=36) or up-front surgery (n=30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient outcomes. RESULTSIn the multi-institutional resection cohort, immune cells exhibited substantial heterogeneity across patient tumors and were located predominantly in stromal regions. Unsupervised clustering using immune cell densities identified four main patterns of immune cell infiltration. One pattern, seen in 20% of tumors and characterized by abundant T cells (T cell-rich) and a paucity of immunosuppressive granulocytes and macrophages, was associated with improved patient survival. Neoadjuvant chemotherapy was associated with a higher CD8:CD4 ratio, greater M1:M2-polarized macrophage ratio, and reduced CD15+ARG1+ immunosuppressive granulocyte density. Within neoadjuvant-treated tumors, 64% showed a T-cell-rich pattern with low immunosuppressive granulocytes and macrophages. M1-polarized macrophages were located closer to tumor cells after neoadjuvant chemotherapy and colocalization of M1-polarized macrophages and tumor cells was associated with greater tumor pathologic response and improved patient survival. CONCLUSIONNeoadjuvant chemotherapy with FOLFIRINOX shifts the PDAC immune microenvironment towards an anti-tumorigenic state associated with improved patient survival.
Details
- Title: Subtitle
- Neoadjuvant chemotherapy is associated with altered immune cell infiltration and an anti-tumorigenic microenvironment in resected pancreatic cancer
- Creators
- Andressa Dias CostaSara A VäyrynenAkhil ChawlaJinming ZhangJuha P VäyrynenMai Chan LauHannah L WilliamsChen YuanVicente Morales-OyarvideDalia ElganainyHarshabad SinghJames M ClearyKimberly PerezKimmie NgWilliam Freed-PastorJoseph D ManciasStephanie K DouganJiping WangDouglas A RubinsonRichard F DunneMargaret M KozakLauren BraisEmma ReillyThomas ClancyDavid C LinehanDaniel T ChangAram F HezelAlbert C KoongAndrew AguirreBrian M WolpinJonathan A Nowak
- Resource Type
- Abstract
- Publication Details
- Clinical cancer research
- DOI
- 10.1158/1078-0432.CCR-22-1125
- PMID
- 36129461
- PMCID
- PMC9999119
- NLM abbreviation
- Clin Cancer Res
- eISSN
- 1557-3265
- Grant note
- name: Finish Cultural Foundation and Orion Research; name: Hale Family Center for Pancreatic Cancer Research; DOI: 10.13039/100005979, name: Lustgarten Foundation; DOI: 10.13039/100000002, name: National Institutes of Health, award: U01 CA224146-01; DOI: 10.13039/100000002, name: National Institutes of Health, award: K08 CA218420-02; DOI: 10.13039/100000002, name: National Institutes of Health, award: P50 CA127003; DOI: 10.13039/100000002, name: National Institutes of Health, award: U01 CA250549; DOI: 10.13039/100000002, name: National Institutes of Health, award: U01 CA210171; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01 CA248857; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01 CA205406; DOI: 10.13039/100000002, name: National Institutes of Health, award: R01 CA169141; DOI: 10.13039/100000002, name: National Institutes of Health, award: R35 CA197735; DOI: 10.13039/100001784, name: Pancreatic Cancer Action Network; DOI: 10.13039/100004336, name: Novartis; name: Bristol-Myers Squibb; name: Genocea; DOI: 10.13039/100000862, name: Doris Duke Charitable Foundation; DOI: 10.13039/100009730, name: Stand Up To Cancer; name: Noble Effort Fund; name: Wexler Family Fund; name: Promises for Purple; name: Bob Parsons Fund
- Language
- English
- Date published
- 09/21/2022
- Academic Unit
- Radiation Oncology
- Record Identifier
- 9984314291302771
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