T Cell–Mediated Antitumor Immunity Cooperatively Induced By TGFβR1 Antagonism and Gemcitabine Counteracts Reformation of the Stromal Barrier in Pancreatic Cancer

Li, Dandan; Schaub, Nicholas P.; Guerin, Theresa M.; Bapiro, Tashinga E.; Richards, Frances M.; Chen, Vicky; Talsania, Keyur; Kumar, Parimal; Gilbert, Debra J.; Schlomer, Jerome; Kim, Seong‐Jin; Sorber, Rebecca; Teper, Yaroslav; Bautista, Wendy; Palena, Claudia; Ock, Chan‐Young; Jodrell, Duncan I.; Pate, Nathan; Mehta, Monika; Zhao, Yongmei; Kozlov, Serguei; Rudloff, Udo

doi:10.1158/1535-7163.mct-20-0620

Cited by 14 publications

(9 citation statements)

References 54 publications

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“…Several preclinical models of solid tumour, including PDAC, demonstrated that halofuginone inhibits collagen synthesis by inhibiting TGF-β signalling [ 80 ]. By reprograming T-regs and stimulating CD8 + T cell-mediated anti-tumour activity, TGF-β inhibition in conjunction with gemcitabine effectively inhibited tumour development [ 81 ]. Of late, it has been revealed that CAFs provide TGF-β to induce tumour progression and chemoresistance by upregulating ATF4 expression [ 82 ].…”

Section: Functions Of Cafsmentioning

confidence: 99%

Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma

et al. 2022

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Pancreatic ductal adenocarcinoma (PDAC) is a lethal cancer with a prominent extracellular matrix (ECM) deposition and poor prognosis. High levels of ECM proteins derived from tumour cells reduce the efficacy of conventional cancer treatment paradigms and contribute to tumour progression and metastasis. As abundant tumour-promoting cells in the ECM, cancer-associated fibroblasts (CAFs) are promising targets for novel anti-tumour interventions. Nonetheless, related clinical trials are hampered by the lack of specific markers and elusive differences between CAF subtypes. Here, we review the origins and functional diversity of CAFs and show how they create a tumour-promoting milieu, focusing on the crosstalk between CAFs, tumour cells, and immune cells in the tumour microenvironment. Furthermore, relevant clinical advances and potential therapeutic strategies relating to CAFs are discussed.

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Section: Functions Of Cafsmentioning

confidence: 99%

Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma

et al. 2022

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“…Additionally, inhibiting TGF-β caused a reduction of Treg-mediated suppression of CD8 + T cells. This suggests that TGF-β could promote the development of effector memory Tregs with suppressive activity against CTL, further highlighting the role of TGF-β in indirectly impairing CTL function in cancer ( 30 ). To conclude, CAFs could potentially mediate induction of Tregs and suppress memory T cells, however, current evidence is not conclusive.…”

Section: Do Cafs Truly Drive Regulatory T Cell Differentiation?mentioning

confidence: 94%

“…Additionally CAFs upregulate SPRY1 in T cells associated with reduced activation and downregulate CD107, and cause a reduction in secretion of Granzyme B and TNF-α. Opposing studies report an increase or decrease of IFN-γ secretion by T cells ( 7 , 30 – 32 ). (F) CAFs upregulate exhaustion markers PD1, Lag3, TIGIT, Tim3and CD39 on T cells ( via e.g.…”

Section: How Do Cafs Restrict T Cell Migration?mentioning

confidence: 99%

“…showed TGF-β inhibition caused a temporary shift from myCAF, which were located tightly around the tumour islands to iCAF which were loosely connected interspersed. Inhibiting TGF-β in combination with gemcitabine, caused an increase in IFN-γ production by CD8 + T cells as well as increased T cell activation markers 4-1BB (CD137) and OX40 and markers of cytotoxicity (granzyme and perforin) ( 30 ).…”

Section: Do Cafs Truly Drive Regulatory T Cell Differentiation?mentioning

confidence: 99%

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Cancer Associated Fibroblasts - An Impediment to Effective Anti-Cancer T Cell Immunity

et al. 2022

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The presence of functionally efficient cytotoxic T lymphocytes (CTL) in the Tumour nest is crucial in mediating a successful immune response to cancer. The detection and elimination of cancer cells by CTL can be impaired by cancer-mediated immune evasion. In recent years, it has become increasingly clear that not only neoplastic cells themselves, but also cells of the tumour microenvironment (TME) exert immunosuppressive functions and thereby play an integral part in the immune escape of cancer. The most abundant stromal cells of the TME, cancer associated fibroblasts (CAFs), promote tumour progression via multiple pathways and play a role in dampening the immune response to cancer. Recent research indicates that T cells react to CAF signalling and establish bidirectional crosstalk that plays a significant role in the tumour immune response. This review discusses the various mechanisms by which the CAF/T cell crosstalk may impede anti-cancer immunity.

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“…Moreover, several chemotherapeutic agents, such as cisplatin, oxaliplatin, doxorubicin, and paclitaxel, can also enhance the expression of immune checkpoints, mostly PD-L1 (Ng et al, 2018). In this context, the expression of PD-L1 on cancer cells can associate with the PD-1 receptor on effector T cells, reducing anti-tumor immune responses and facilitating immune escape (Li et al, 2021).…”

Section: Chemotherapy Combined With Pd-l1/pd-1 Inhibitorsmentioning

confidence: 99%

Combinatorial regimens of chemotherapeutic agents: A new perspective on raising the heat of the tumor immune microenvironment

Liu

Gao

et al. 2022

Front. Pharmacol.

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Harnessing the broad immunostimulatory capabilities of chemotherapy in combination with immune checkpoint inhibitors has improved immunotherapy outcomes in patients with cancer. Certain chemotherapeutic agents can extensively modify the tumor microenvironment (TME), resulting in the reprogramming of local immune responses. Although chemotherapeutic agents with an enhanced generation of potent anti-tumor immune responses have been tested in preclinical animal models and clinical trials, this strategy has not yet shown substantial therapeutic efficacy in selected difficult-to-treat cancer types. In addition, the efficacy of chemotherapeutic agent-based monotherapy in eliciting a long-term anti-tumor immune response is restricted by the immunosuppressive TME. To enhance the immunomodulatory effect of chemotherapy, researchers have made many attempts, mainly focusing on improving the targeted distribution of chemotherapeutic agents and designing combination therapies. Here, we focused on the mechanisms of the anti-tumor immune response to chemotherapeutic agents and enumerated the attempts to advance the use of chemo-immunotherapy. Furthermore, we have listed the important considerations in designing combinations of these drugs to maximize efficacy and improve treatment response rates in patients with cancer.

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T Cell–Mediated Antitumor Immunity Cooperatively Induced By TGFβR1 Antagonism and Gemcitabine Counteracts Reformation of the Stromal Barrier in Pancreatic Cancer

Abstract: for their contributions and generous support for the single cell RNA sequencing work of the KPC tumors.

Cited by 14 publications

References 54 publications

Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma

Cancer-associated fibroblasts in pancreatic ductal adenocarcinoma

Cancer Associated Fibroblasts - An Impediment to Effective Anti-Cancer T Cell Immunity

Combinatorial regimens of chemotherapeutic agents: A new perspective on raising the heat of the tumor immune microenvironment

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