Immunity, inflammation, and cancer: an eternal fight between good and evil

Abstract

Cancer development and its response to therapy are strongly influenced by innate and adaptive immunity, which either promote or attenuate tumorigenesis and can have opposing effects on therapeutic outcome. Chronic inflammation promotes tumor development, progression, and metastatic dissemination, as well as treatment resistance. However, cancer development and malignant progression are also associated with accumulation of genetic alterations and loss of normal regulatory processes, which cause expression of tumor-specific antigens and tumor-associated antigens (TAAs) that can activate antitumor immune responses. Although signals that trigger acute inflammatory reactions often stimulate dendritic cell maturation and antigen presentation, chronic inflammation can be immunosuppressive. This antagonism between inflammation and immunity also affects the outcome of cancer treatment and needs to be considered when designing new therapeutic approaches.

Figure 2. Acute inflammation promotes antitumor immunity in response to immunogenic chemotherapy in noninflamed tumors.

ICD is induced by injury, stress, and certain chemotherapeutic agents. ICD can induce expression of surface calreticulin and HMGB1 in cancer cells, thereby activating innate immune cells through PRRs. DC maturation and antigen cross-presentation, together with secretion of inflammatory cytokines, can efficiently prime cytotoxic T cells, resulting in effective antitumor immune responses. However, in tumors with a chronically inflamed microenvironment rich in immunosuppressive factors, antitumor immunity cannot be activated unless the immunosuppressive factors are neutralized or eliminated.

Figure 1. Inflammation promotes tumor development.

(A) Microbial products that penetrate through the defective barrier associated with early tumors or DAMPs released by dying cancer cells (CACs) activate myeloid cells that are recruited into the tumor due to production of chemokines by CACs. (B) TAMs and TANs express cytokines, such as IL-1, IL-6, and TNF, which act directly on CACs, leading to activation of NF-κB, STAT3, YAP, and Notch. The cytokines thereby promote CAC survival and proliferation. (C) The growing tumor secretes lactate and acquires a hypoxic core due to insufficient O₂ supply. The hypoxia results in CAF activation due to HIF-1–induced TGF-β production and may convert TAM1 cells to a TAM2 phenotype, which produces VEGF to support neo-angiogenesis. (D) CAFs, which express TGF-β and CXCL13, recruit lymphotoxin-producing B2 cells that support further tumor growth. (E) Chemokines expressed in the inflamed tumor bed recruit tumor-promoting Th17 cells and immunosuppressive Tregs and MDSCs. (F) Tumor-infiltrating B cells undergo class-switch recombination (CSR) and become ISPCs that induce an exhausted/angergic-like phenotype in cytotoxic T cells.