Kras and Tumor Immunity: Friend or Foe?

Abstract

With the recent breakthroughs in immunotherapy as curative treatments in certain tumor types, there has been renewed interest in the relationship between immunity and tumor growth. Although we are gaining a greater understanding of the complex interplay of immune modulating components in the tumor microenvironment, the specific role that tumor cells play in shaping the immune milieu is still not well characterized. In this review, we focus on how mutant Kras tumor cells contribute to tumor immunity, with a specific focus on processes induced directly or indirectly by the oncogene.

Figure 1.

Main mediators of immune modulation in the tumor microenvironment (TME). Tumor-associated macrophages (TAMs), regulatory T (Treg) cells, regulatory B (Breg) cells, and myeloid-derived suppressor cells (MDSCs) induce a tumor-tolerant microenvironment through production of immune suppressive cytokines like interleukin (IL)-10, IL-35, and transforming growth factor β (TGF-β). These factors antagonize the tumoricidal activity of T helper (Th)1 cells, T cytotoxic (Tc) cells, and natural killer (NK) cells that produce immune stimulatory cytokines and cytolytic factors. MHC, Major histocompatibility complex; iNOS, inducible nitric oxide synthase; ARG1, arginase 1; TNF-α, tumor necrosis factor α; IFN-γ, interferon γ.

Figure 2.

Secreted immunomodulatory factors transcriptionally induced by oncogenic Kras signaling. Transforming growth factor β (TGF-β) and granulocyte macrophage colony-stimulating factor (GM-CSF) are regulated via the concerted action of mitogen-activated protein kinases (MAPKs) and PI3K pathways, interleukin (IL)-10 is regulated via the MAPK pathway, CXCL8 is induced by both MAPK and canonical nuclear factor (NF)-κB pathways, IL-6 is regulated by the noncanonical RalB/TBK1/IKKE/NF-κB pathway, and CXCL1, CXCL2, and CXCL5 are induced via the classical NF-κB signaling pathway.

Figure 3.

Cooperation of Kras-mutant tumor cells with pancreatic stellate cells in tumor microenvironment (TME) immunomodulation. Kras-mutant tumor-cell-derived transforming growth factor β (TGF-β) induces the activation of pancreatic stellate cells (PSCs) in the pancreatic TME, resulting in mitogen-activated protein kinase (MAPK) pathway activation and induction of TGF-β transcription and secretion by PSCs. Increased TGF-β levels can both promote T regulatory (Treg) recruitment and macrophage M2 polarization, thereby contributing to immunosuppression in the TME. Similarly, interleukin (IL)-6 produced by Kras-mutant tumor cells binds to IL-6 receptors on PSCs, resulting in intracellular signal transducers and activators of transcription 3 (STAT3) activation and IL-6 transcription and secretion into the TME. High IL-6 levels amplify the recruitment and M2 polarization of macrophages, thereby promoting tumor growth. Although the mechanism of transcriptional induction of IL-10, granulocyte macrophage colony-stimulating factor (GM-CSF), CXCL10, and CXCL12 by PSCs has not been directly addressed, their secretion by PSCs cooperates with IL-10, GM-CSF, CXCL10, and CXCL12 derived from Kras-mutant tumor cells to amplify Treg cell recruitment (CXCL10), dampen CD8⁺ T-cell responses (CXCL12), or promote macrophage M2 polarization (IL-10, GM-CSF) in the pancreatic TME. NF-κB, Nuclear factor κB.