Context-Specific Determinants of the Immunosuppressive Tumor Microenvironment in Pancreatic Cancer

Abstract

Immunotherapies have shown benefits across a range of human cancers, but not pancreatic ductal adenocarcinoma (PDAC). Recent evidence suggests that the immunosuppressive tumor microenvironment (TME) constitutes an important roadblock to their efficacy. The landscape of the TME differs substantially across PDAC subtypes, indicating context-specific principles of immunosuppression. In this review, we discuss how PDAC cells, the local TME, and systemic host and environmental factors drive immunosuppression in context. We argue that unraveling the mechanistic drivers of the context-specific modes of immunosuppression will open new possibilities to target PDAC more efficiently by using multimodal (immuno)therapeutic interventions.

Significance: Immunosuppression is an almost universal hallmark of pancreatic cancer, although this tumor entity is highly heterogeneous across its different subtypes and phenotypes. Here, we provide evidence that the diverse TME of pancreatic cancer is a central executor of various different context-dependent modes of immunosuppression, and discuss key challenges and novel opportunities to uncover, functionalize, and target the central drivers and functional nodes of immunosuppression for therapeutic exploitation.

Figure 1.

Heterogeneity of TME composition and organization, and context-specific modes of immunosuppression across patients with PDAC. A–C, PDAC patients show profound differences in the cellular composition and organization of the TME, which results in distinct TME subtypes (A), cell-to-cell interaction and communication (B), and function (C). As a consequence, different modes of immunosuppression exist in distinct TME subtypes of PDAC (C). Functions of the cell-to-cell interactions highlighted in yellow in B are depicted in C. Left, CSF1R⁺ tumor-associated macrophages (TAM) are recruited to the tumor via cancer cell–derived secretion of CSF1, thereby promoting an immunosuppressive TME and inhibiting T-cell function. Middle, CXCL12 released by cancer-associated fibroblasts (CAF) prevents T-cell tumor infiltration. Right, neoantigens released by dying cancer cells in the TME are captured by dendritic cells for processing. After homing to the lymphoid organs, dendritic cells present the neoantigens to T cells, inducing their priming, activation, and clonal expansion. Activated T cells migrate into the TME, where they can exert anticancer immune responses through secretion of molecules such GZMB and IFNγ. However, immunosuppressive mechanisms controlled by the cancer cells, such as activation of immune checkpoints (e.g., PD-L1 or TIGIT), render them dysfunctional, thereby allowing tumor cells to evade immune destruction. D, PDAC patients with a high content of myeloid cells in the TME have a worse disease prognosis, whereas patients with tumors with high lymphocytes have a better overall survival. ECM, extracellular matrix; MDSC, myeloid-derived suppressor cell; Treg, regulatory T cell.

Figure 2.

The context-specific composition and function of the immunosuppressive TME are controlled by tumor cell–intrinsic cues, as well as non–tumor cell–autonomous factors of the host. A, Context-dependent features of the host, such as genetic variation, acute and chronic infection, inflammation and injury, nutrition and metabolism, diabetes and obesity, environmental toxins, and composition of the microbiome, virome, and fungome, affect immune escape and immunosuppression. These factors constitute fundamental determinants of PDAC heterogeneity. B, Cancer cells of different PDAC subtypes and associated tumor cell–intrinsic signaling programs instruct their corresponding TME and drive immunosuppression. Classical and mesenchymal basal-like PDAC differ in cell morphology, gene expression programs, KRAS dosage, and stromal content, resulting in tumor entities with unique features that drive differences in the composition and function of their immunosuppressive TME (11, 95, 96). C, Tumor cell states, with distinct levels of Kras dosage, show differences in infiltrating immune cells and their TME. Classical tumors display high TME diversity and infiltration of SPP1⁺ TAMs, intermediate coexpressor tumors show high T-cell infiltration, and basal-like tumors are characterized by infiltration of C1QC⁺ TAMs (152).

Figure 3.

Therapy-induced reprogramming of PDAC subtypes and their immunosuppressive TME. A, Basal-like mesenchymal PDAC relies on BRD4-dependent cJUN/AP1 expression, which induces CCL2. CCL2 secretion leads to the recruitment of TNFα-secreting macrophages, which promote reprogramming of classical tumor cells into basal-like mesenchymal ones and maintenance of the mesenchymal state. The use of BRD4 inhibitors such as JQ1 suppresses the BRD4–cJUN–CCL2–TNFα axis and induces redifferentiation of the mesenchymal to the classical PDAC subtype, which is characterized by a more favorable prognosis (151). B, Classical and basal-like mesenchymal PDAC are driven by tumor cell–intrinsic cues (e.g., KRAS dosage), and their TME is characterized by distinct immune cell infiltrates. This results in a differential response to a combinatorial therapy of the MEK inhibitor trametinib and the multikinase inhibitor nintedanib (T/N). The combination promotes the context-dependent reprogramming of the tumor cell secretome, thereby inducing a subtype-specific TME remodeling. In the classical subtype, T/N induces infiltration of MDSCs/neutrophils and M1-like TAMs and does not sensitize the tumors to anti–PD-L1 ICB. In basal-like mesenchymal PDAC, T/N leads to the recruitment of M1-like TAMs and CD8⁺ T cells, sensitizing the tumors to anti–PD-L1 ICB (96).