Overcoming immunotherapeutic resistance by targeting the cancer inflammation cycle

Abstract

Inflammation is a hallmark of cancer and supports tumor growth, proliferation, and metastasis, but also inhibits T cell immunosurveillance and the efficacy of immunotherapy. The biology of cancer inflammation is defined by a cycle of distinct immunological steps that begins during disease conception with the release of inflammatory soluble factors. These factors communicate with host organs to trigger bone marrow mobilization of myeloid cells, trafficking of myeloid cells to the tumor, and differentiation of myeloid cells within the tumor bed. Tumor-infiltrating myeloid cells then orchestrate an immunosuppressive microenvironment and assist in sustaining a vicious cycle of inflammation that co-evolves with tumor cells. This Cancer-Inflammation Cycle acts as a rheostat or "inflammostat" that impinges upon T cell immunosurveillance and prevents the development of productive anti-tumor immunity. Here, we define the major nodes of the Cancer-Inflammation Cycle and describe their impact on T cell immunosurveillance in cancer. Additionally, we discuss emerging pre-clinical and clinical data suggesting that intervening upon the Cancer-Inflammation Cycle will be a necessary step for broadening the potential of immunotherapy in cancer.

Keywords: Cancer; Immunotherapy; Inflammation; Inflammostat; Macrophage; Myeloid cells; T cells.

Figure 1.. The Cancer-Inflammation Cycle.

Cancer inflammation is a cyclic process that is initiated at disease conception. The cycle is dynamic and evolves with cancer progression. This cycle can be divided into six major steps, starting with the release of pro-inflammatory signals that elaborate the mobilization (from bone marrow or adjacent tissues), recruitment, and differentiation of myeloid cells. Tumor-infiltrating myeloid cells then orchestrate a microenvironment that is supportive of cancer growth, metastasis, immune evasion, and therapeutic resistance. Each step is described above, with the anatomic location of each immunologic event given including processes occurring extra-tumoral (grey), intra-tumoral (blue), and within draining lymph nodes (orange).

Figure 2.. Graphical representation of the Inflammatory Contexture and Inflammostat.

The inflammatory contexture is defined as the type, polarity, intensity, and location of cancer inflammation. Parameters comprising the inflammatory contexture include myeloid cell subsets detected within the blood and tumor (type), the functional phenotype of myeloid cells (polarity), and the intensity of the inflammatory response (intensity) determined by cell density within tumors and the magnitude of inflammatory factors present within the bloodstream (location). The immunostat, a rheostat of the inflammatory reaction, is derived from the magnitude and polarity of the inflammatory contexture and serves as a fundamental regulator of immunosurveillance. A high inflammostat signifies an immunological state that is unlikely to respond to therapies that seek to solely engage T cell immunosurveillance by derailing immune checkpoints (e.g. CTLA4 and PD1/PDL1). The functional orientation of the inflammatory contexture is characterized by proteins and their activation status (e.g. phosphorylation) that predict the phenotype of inflammatory cells (e.g. immunostimulatory or immunosuppressive) and that associate with responses to immunotherapy. Shown are a select set of proposed determinants and their association with immune suppression (blue) or stimulation (red). Abbreviations: CRP, c-reactive protein; CXCL/CCL, chemokine motif ligands; IFNG, interferon gamma; IRF8, interferon regulatory factor 8; IL, interleukin; PDL1, programmed death-ligand 1; SAA, serum amyloid A; STAT, signal transducer and activator of transcription.

Figure 3.. Regulatory factors that shape the Cancer-Inflammation Cycle.

Each step of the Cancer-Inflammation Cycle is coordinated by an array of factors. Factors shown in green may stimulate anti-tumor immunity, whereas factors shown in red engage an inflammatory response that more commonly suppresses anti-tumor immunity. Factors that are in black may support either the stimulation or suppression of anti-tumor immunity. Together, these factors contribute to the inflammatory contexture of cancer and establish an inflammatory rheostat (“inflammostat”). In addition, these factors identify potential therapeutic targets that may be derailed to disrupt the Cancer-Inflammation Cycle as a strategy to disengage the pro-tumorigenic potential of inflammation and redirect the inflammatory response with immunostimulatory properties. Abbreviations: CSF1, colony stimulating factor 1; IL, interleukin; CXCL/CCL, chemokine motif ligands; FAK, focal adhesion kinase; FLT3Lg, Fms related tyrosine kinase 3 ligand; ICAM, intracellular adhesion molecule; IDO, indoleamine 2,3-dioxgenase; IFN, interferon; MAdCAM-1, mucosal addressin cell adhesion molecule 1; MMP, matrix metalloproteinase; TLR, toll like receptor; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule.