Neoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile in pancreatic cancer

Heiduk, Max; Plesca, Ioana; Gluck, Jessica M.; Müller, Luise; Digomann, David; Reiche, Charlotte; Renesse, Janusz von; Decker, Rahel; Kahlert, Christoph; Sommer, Ulrich; Aust, Daniela E.; Schmitz, Marc; Weitz, Jürgen; Seifert, Lena; Seifert, Adrian M.

doi:10.1172/jci.insight.152761

Cited by 12 publications

(17 citation statements)

References 45 publications

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“…An immunotherapeutic approach should be considered only in tumors with a high mutational burden, as found in tumors with mismatch repair deficiency (dMMR, <1% of all PDAC) [ 5 , 6 , 7 , 8 , 9 ]. An immune suppressive tumor microenvironment with low levels of neoantigens, constrained levels of effector T cells, altered tumor stroma, and a high number of suppressive myeloid cells prevents a sufficient antitumoral immune response [ 10 , 11 , 12 , 13 , 14 ]. In more than two-thirds of all PDACs, an immune-exhausted environment was associated with reduced overall survival [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

VISTA Ligation Reduces Antitumor T-Cell Activity in Pancreatic Cancer

Digomann

Strack

Heiduk

et al. 2023

Cancers

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Immunotherapy has shown promising results in multiple solid tumors and hematological malignancies. However, pancreatic ductal adenocarcinoma (PDAC) has been largely refractory to current clinical immunotherapies. The V-domain Ig suppressor of T-cell activation (VISTA) inhibits T-cell effector function and maintains peripheral tolerance. Here, we determine VISTA expression in nontumorous pancreatic (n = 5) and PDAC tissue using immunohistochemistry (n = 76) and multiplex immunofluorescence staining (n = 67). Additionally, VISTA expression on tumor-infiltrating immune cells and matched blood samples (n = 13) was measured with multicolor flow cytometry. Further, the effect of recombinant VISTA on T-cell activation was investigated in vitro, and VISTA blockade was tested in an orthotopic PDAC mouse model in vivo. PDAC showed significantly higher VISTA expression compared to that of a nontumorous pancreas. Patients with a high density of VISTA-expressing tumor cells had reduced overall survival. The VISTA expression of CD4+ and CD8+ T cells was increased after stimulation and particularly after a coculture with tumor cells. We detected a higher level of proinflammatory cytokine (TNFα and IFNγ) expression by CD4+ and CD8+ T cells, which was reversed with the addition of recombinant VISTA. A VISTA blockade reduced tumor weights in vivo. The VISTA expression of tumor cells has clinical relevance, and its blockade may be a promising immunotherapeutic strategy for PDAC.

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Section: Introductionmentioning

confidence: 99%

VISTA Ligation Reduces Antitumor T-Cell Activity in Pancreatic Cancer

Digomann

Strack

Heiduk

et al. 2023

Cancers

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“…This result is consistent with others revealing that neoadjuvant chemotherapy with FOLFIRINOX enhances effector T cells and downregulates suppressor cells in peripheral blood. Heiduk et al [10] found that the tendency of conventional CD4+ T cells and Tregs (the frequency of conventional CD4+ T cells was increased, and the proportion of Tregs was reduced) was similar in the TME and peripheral blood in neoadjuvant FOLFIRINOX-treated arm compared with treatment naïve arm, further suggesting that peripheral situations could partly reflect the TME conditions. It makes it possible and convenient for us to explore dynamic profiling of the TME during neoadjuvant chemotherapy courses in the same patient since blood is easier to obtain than matched tumor specimens.…”

Section: Recruited Anti-tumor Immune Cells From Progenitor Cell Diffe...mentioning

confidence: 99%

Section: Recruited Anti-tumor Immune Cells From Progenitor Cell Diffe...mentioning

confidence: 99%

“…Quantitatively, numerous studies demonstrated that neoadjuvant chemotherapy could elevate cytotoxic lymphatic cell (i.e., CD8+ T cells, conventional CD4+ T cells, and NK cells) and decline immunosuppressive myeloid cells (M2-skewed cells and myeloid-derived suppressor cells) infiltration, creating an anti-tumorigenic microenvironment [10,26,28,29] and a tendency to reverse natural tumor progression in pancreatic cancer.…”

Section: Reshaped Tumor Immune Cells In Quantity Space and Functionmentioning

confidence: 99%

“…The tumor microenvironment (TME) of pancreatic cancer, mainly comprising cancer cells, cancer-associated fibroblasts (CAFs), and immune cells, is dynamic during natural tumor progression and chemotherapeutic treatment (Figure 1) [10][11][12]. The number of ductal cells gradually decreased with tumor stage (I-II-III) progression (44.88%-36.04%-18.95%) [11].…”

Section: Introductionmentioning

confidence: 99%

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Reshaping the Pancreatic Cancer Microenvironment at Different Stages with Chemotherapy

Peng

Ying

Zhang

et al. 2023

Cancers

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The dynamic tumor microenvironment, especially the immune microenvironment, during the natural progression and/or chemotherapy treatment is a critical frontier in understanding the effects of chemotherapy on pancreatic cancer. Non-stratified pancreatic cancer patients always receive chemotherapeutic strategies, including neoadjuvant chemotherapy and adjuvant chemotherapy, predominantly according to their physical conditions and different disease stages. An increasing number of studies demonstrate that the pancreatic cancer tumor microenvironment could be reshaped by chemotherapy, an outcome caused by immunogenic cell death, selection and/or education of preponderant tumor clones, adaptive gene mutations, and induction of cytokines/chemokines. These outcomes could in turn impact the efficacy of chemotherapy, making it range from synergetic to resistant and even tumor-promoting. Under chemotherapeutic impact, the metastatic micro-structures in the primary tumor may be built to leak tumor cells into the lymph or blood vasculature, and micro-metastatic/recurrent niches rich in immunosuppressive cells may be recruited by cytokines and chemokines, which provide housing conditions for these circling tumor cells. An in-depth understanding of how chemotherapy reshapes the tumor microenvironment may lead to new therapeutic strategies to block its adverse tumor-promoting effects and prolong survival. In this review, reshaped pancreatic cancer tumor microenvironments due to chemotherapy were reflected mainly in immune cells, pancreatic cancer cells, and cancer-associated fibroblast cells, quantitatively, functionally, and spatially. Additionally, small molecule kinases and immune checkpoints participating in this remodeling process caused by chemotherapy are suggested to be blocked reasonably to synergize with chemotherapy.

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The immune microenvironment after neoadjuvant therapy compared to upfront surgery in patients with pancreatic cancer

Zwart,

van Ee,

Doppenberg

et al. 2023

J Cancer Res Clin Oncol

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Background Patients with resectable and borderline resectable pancreatic ductal adenocarcinoma increasingly receive neoadjuvant therapy prior to surgery. However, the effect of neoadjuvant therapy on the immune microenvironment remains largely unknown. We analyzed the immune microenvironment in pancreatic cancer tumor tissue samples from patients treated with neoadjuvant therapy compared to patients after upfront surgery to gain knowledge about the immunological environment after therapy. Methods Multispectral imaging was performed on tissue from resected specimens from patients with PDAC who underwent upfront surgery (n = 10), neoadjuvant FOLFIRINOX (n = 10) or gemcitabine + radiotherapy (gem-RT) (n = 9) followed by surgery. The samples were selected by a dedicated pancreas pathologist from both the central part and the invasive front of the tumor (by the resected vein or venous surface) and subsequently analyzed using the Vectra Polaris. Results Patients receiving neoadjuvant FOLFIRINOX display a more pro-inflammatory immune profile, with less regulatory T cells and more CD8 T cells in the tumor tissue compared to patients receiving neoadjuvant gem-RTgem-RT or undergoing upfront surgery. Furthermore, CD163+ macrophages were decreased, and a higher CD163− macrophages versus CD163+ macrophages ratio was found in patients with neoadjuvant FOLFIRINOX. In all treatment groups, percentage of FoxP3+ B cells was significantly higher in tumor tissue compared to adjacent tissue. Furthermore, an increase in regulatory T cells in the tumor tissue was found in patients undergoing upfront surgery or receiving neoadjuvant gem-RT. In the gem-RT group, less CD8 T cells and a higher CD163+ macrophages to CD8 ratio were noted in the tumor tissue, suggesting a more immune suppressive profile in the tumor tissue. Conclusion Patients receiving neoadjuvant FOLFIRINOX display a more pro-inflammatory immune profile compared to patients receiving neoadjuvant gem-RT or undergoing upfront surgery. Furthermore, in all treatment groups, a more immune suppressive microenvironment was found in the tumor tissue compared to the adjacent non-tumorous tissue.

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Neoadjuvant chemotherapy drives intratumoral T cells toward a proinflammatory profile in pancreatic cancer

Cited by 12 publications

References 45 publications

VISTA Ligation Reduces Antitumor T-Cell Activity in Pancreatic Cancer

VISTA Ligation Reduces Antitumor T-Cell Activity in Pancreatic Cancer

Reshaping the Pancreatic Cancer Microenvironment at Different Stages with Chemotherapy

The immune microenvironment after neoadjuvant therapy compared to upfront surgery in patients with pancreatic cancer

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