Characterization of spatial distribution of tumor-infiltrating CD8+ T cells refines their prognostic utility for pancreatic cancer survival

Masugi, Yohei; Abe, Tokiya; Ueno, Akihisa; Fujii-Nishimura, Yoko; Ojima, Hidenori; Endo, Yutaka; Fujita, Yusuke; Kitago, Minoru; Shinoda, Masahiro; Kitagawa, Yuko; Sakamoto, Michiie

doi:10.1038/s41379-019-0291-z

Cited by 92 publications

(85 citation statements)

References 59 publications

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“…These findings are in line with previous studies on pancreatic cancer . A recent study by Masugi et al ., could not establish a significant association between CD8 + T‐cell proximity to cancer cells and patient survival, however, our study used a different methodology . They did, however, find a significant association between patient survival and CD8 + T‐cell infiltration in the tumor center, further supporting that the topographic infiltration patterns of CD8 + cells are of prognostic importance .…”

Section: Discussioncontrasting

confidence: 58%

Quantitative, qualitative and spatial analysis of lymphocyte infiltration in periampullary and pancreatic adenocarcinoma

Lundgren

Elebro

Heby

et al. 2020

Intl Journal of Cancer

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Immunotherapeutic modalities are currently revolutionizing cancer treatment. In pancreatic cancer, however, early clinical trials have been disappointing. The optimization of immunotherapeutic strategies requires better understanding of the inflammatory tumor microenvironment. Therefore, the aim of our study was to perform a detailed in situ description of lymphocyte infiltration patterns in resected pancreatic and other periampullary cancers. Multiplexed immunofluorescence imaging was applied to tissue microarrays with tumors from a cohort of 175 patients with resected periampullary adenocarcinoma. A panel of immune cell markers including CD4, CD8α, FoxP3, CD20, CD45RO and pan-cytokeratin was applied to allow for simultaneous spatial analysis of multiple lymphocyte populations. The majority of lymphocyte populations were significantly more abundant in intestinal (I-type) compared to pancreatobiliary (PB-type) tumors. Hierarchical cluster analysis revealed several immune cell signatures of potential clinical relevance. Notably, in the stromal compartment of PB-type tumors, high infiltration of B cells, CD8α + CD45RO + and single-positive CD4 + T cells, but low levels of FoxP3 + CD45RO high and single-positive CD8α + T cells were associated with improved overall survival (OS). The study also defined prognostic relevant topographical patterns of lymphocytic infiltration, in particular proximity of CD8α + cells to cancer cells. Moreover, the presence of lymphocytes with potential T-helper capacities (CD4 + ) in the nearest vicinity to CD8α + cells was associated with a prolonged OS. Our data demonstrate that the composition and clinical impact of immune infiltrates in periampullary adenocarcinoma differ by morphological type as well as localization. Furthermore, spatial in situ analysis identified potential immunological mechanisms of prognostic significance.Additional Supporting Information may be found in the online version of this article.

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Section: Discussioncontrasting

confidence: 58%

Quantitative, qualitative and spatial analysis of lymphocyte infiltration in periampullary and pancreatic adenocarcinoma

Lundgren

Elebro

Heby

et al. 2020

Intl Journal of Cancer

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“…In the current dataset, no tumor showed complete absence of nuclear TP53 expression. For SMAD4, tumors were classified as “intact” if there was nuclear/cytoplasmic staining within the tumor, or “lost” if there was complete absence of staining, as previously described . No tumor had missing information on IHC data.…”

Section: Methodsmentioning

confidence: 99%

Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

et al. 2020

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There are increased opportunities in oncology clinics to identify multiple pancreatic ductal adenocarcinomas (PDAC) that co‐occur simultaneously or arise metachronously in the pancreatic parenchyma, yet their pathogenesis remains elusive. We hypothesized that two potential pathways, multicentric carcinogenesis and intrapancreatic metastasis, might contribute to forming multiple PDAC. Among 241 resected cases, we identified 20 cancer nodules from nine patients with multiple PDAC (six with synchronous PDAC, one with metachronous PDAC, and two with both synchronous and metachronous PDAC). Integrated clinical, pathological, and mutational analyses, using TP53 and SMAD4 immunostaining and targeted next‐generation sequencing of 50 cancer‐related genes, were conducted to examine the intertumor relationships. Four of the nine patients were assessed as having undergone multicentric carcinogenesis because of heterogeneity of immunohistochemical and/or mutation characteristics. In contrast, tumors in the other five patients showed intertumor molecular relatedness. Two of these five patients, available for matched sequencing data, showed two or more shared mutations. Moreover, all the smaller nodules in these five patients showed identical TP53 and SMAD4 expression patterns to the corresponding main tumors. Consequently, these five patients were considered to have undergone intrapancreatic metastasis. None of the five smaller nodules arising from intrapancreatic metastasis was accompanied by pancreatic intraepithelial neoplasia, and three of them were tiny (≤1mm). Patients whose tumors resulted from intrapancreatic metastasis appeared to have higher disease stages and worse outcome than those with tumors from multicentric carcinogenesis. Our results provide insight into pancreatic carcinogenesis, showing that the development of multiple PDAC involves distinct evolutionary paths that potentially affect patient prognosis.

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“…After adjustment for immune density, only MH-based tumor subtypes remained significantly associated with CRC-specific survival but not G-cross. Masugi et al also pointed out that L-cross function is limited by the underlying assumption that tumor cells are treated as isolated entities, without considering tumor morphology like ductular structures in pancreatic adenocarcinoma 12,20 . To capture the highly heterogeneous tumor-immune cell interactions within a TME, TIPC employs novel spatial measures quantified on tessellated sub-regions.…”

Section: Discussionmentioning

confidence: 99%

Tumor-Immune Partitioning and Clustering (TIPC) algorithm reveals distinct signatures of tumor-immune cell interactions within the tumor microenvironment

Lau

Borowsky²,

Väyrynen

et al. 2020

Preprint

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Growing evidence supports the importance of understanding tumor-immune spatial relationship in the tumor microenvironment in order to achieve precision cancer therapy.However, existing methods, based on oversimplistic cell-to-cell proximity, are largely confounded by immune cell density and are ineffective in capturing tumor-immune spatial patterns. Here we developed a novel computational algorithm, termed Tumor-Immune Partitioning and Clustering (TIPC), to offer an effective solution for spatially informed tumor subtyping. Our method could measure the extent of immune cell partitioning between tumor epithelial and stromal areas as well as the degree of immune cell clustering. Using a U.S. nation-wide colorectal cancer database, we showed that TIPC could determine tumor subtypes with unique tumor-immune spatial patterns that were significantly associated with patient survival and key tumor molecular features. We also demonstrated that TIPC was robust to parameter settings and readily applicable to different immune cell types. The capability of TIPC in delineating clinically relevant patient subtypes that encapsulate tumor-immune spatial relationship, immune density, and tumor morphology is expected to shed light on underlying immune mechanisms. Hence, TIPC can be a useful bioinformatics tool for effective characterization of the spatial composition of the tumor-immune microenvironment to inform precision immunotherapy.

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Characterization of spatial distribution of tumor-infiltrating CD8+ T cells refines their prognostic utility for pancreatic cancer survival

Cited by 92 publications

References 59 publications

Quantitative, qualitative and spatial analysis of lymphocyte infiltration in periampullary and pancreatic adenocarcinoma

Quantitative, qualitative and spatial analysis of lymphocyte infiltration in periampullary and pancreatic adenocarcinoma

Pathogenesis of multiple pancreatic cancers involves multicentric carcinogenesis and intrapancreatic metastasis

Tumor-Immune Partitioning and Clustering (TIPC) algorithm reveals distinct signatures of tumor-immune cell interactions within the tumor microenvironment

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