Clinically feasible and prospective immunotherapeutic interventions in multidirectional comprehensive treatment of cancer

Inflammation Control and Immunotherapeutic Strategies in Comprehensive Cancer Treatment

“…“Overheating” tumors due to disproportionate tumor-driven inflammation can thwart the effectiveness of immunotherapeutic interventions. Indeed, inflammation, on one hand, attracts anti-tumor immune cells to TME, and on the other hand, excessive inflammation creates favorable conditions for tumor growth and metastasis, notably by upregulating the expression of checkpoint inhibitory molecule expression and promoting the migration and functionality of pro-tumor immune cells [ 4 ]. Therefore, combination therapy of advanced cancers should necessarily include anti-inflammatory therapy conducive to “cooling down” exaggerated tumor-mediated inflammation and to dampen pro-tumor immune activity [ 17 ] by drugs such as cyclooxygenase-2 (COX-2) inhibitors, H2-blockers, phosphodiesterase-5 (PDE-5) inhibitors, statins, activator of AMP-activated protein kinase, and glucocorticoids [ 4 , 16 ].…”

“…Moreover, anti-tumor immune responses are commonly boosted by mAb-based inactivation of immunosuppressive checkpoint molecules [PD-1/PD-L1, cytotoxic T lymphocyte-associated antigen-4 (CTLA-4), lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin and mucin-domain containing-3 (TIM-3), T cell immunoglobulin and ITIM domain (TIGIT), V-domain Ig suppressor of T cell activation (VISTA), etc. ], which are known to suppress the activation and function of T cells and downregulate immune (including anti-cancer) reactivity [ 4 , 18 ]. However, while PD-1/PD-L1 and CTLA-4 immune checkpoint molecule blockade holds great promise as an effective immunotherapeutic approach to treat cancer in experimental and clinical conditions displaying different degrees of success in some cancers including melanoma, non-small cell lung carcinoma (NSCLC), and urothelial carcinoma, many reports have shown low or no responsiveness in other cancer types such as gastrointestinal, breast, pancreatic, prostate, sarcoma, and colorectal cancers [ 9 ].…”

“…In this paradigm, professional antigen (Ag), presenting cells DCs and macrophages, cleave endogenous and exogenous Ags to small antigenic peptides for binding to, and presentation by, major histocompatibility (MHC) class I and class II molecules, resulting in the clonal expansion of CD8+ and CD4+T cells, respectively. Principal T cells with anti-tumor activity (i.e., Th1 cells) are characterized by the ability to promote cell-mediated CD8+ cytotoxic T lymphocyte (CTL) generation, classical macrophage (M1) and neutrophil (N1) activation as well as the activation of other effector cells with cytotoxic potential such as NK cells, NKT cells, and γδ T cells [ 3 , 4 ].…”

“…Pro-tumor innate immunity is based on alternatively activated neutrophils (N2) and (M2) macrophages, myeloid-derived suppressor cells (MDSCs), and innate regulatory T (Tregs) and B cells (Bregs), whereas adaptive immunity is mediated via adaptive Tregs and Th2 cells. Th2 cells facilitate the activation of M2 macrophages, N2 neutrophils, and myeloid-derived suppressor cells (MDSCs) [ 3 , 4 ], and have the ability to directly and indirectly suppress the functional activity of Th1 cells and vice versa, which allows for the sustained polarization of immune reactivity [ 5 ].…”

“…Bifunctionality of IL-2, a well-known T cell growth and differentiation factor, reveals itself in stimulating Th1 cells and CTL with anti-tumor activity, but at the same time, serving as a potent activator of Tregs, which inhibits immune-mediated anti-tumor activity [ 3 ]. On one hand, granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pivotal molecule in the generation of mature DCs that trigger adaptive immune responses, but on the other hand, it is also an inductor and activator of immunosuppressive MDSCs [ 3 , 4 ].…”