Cancer Immunotherapy: Whence and Whither

Abstract

The current concepts and practice of cancer immunotherapy evolved from classical experiments that distinguished "self" from "non-self" and the finding that humoral immunity is complemented by cellular immunity. Elucidation of the biology underlying immune checkpoints and interactions between ligands and ligand receptors that govern the immune system's ability to recognize tumor cells as foreign has led to the emergence of new strategies that mobilize the immune system to reverse this apparent tolerance. Some of these approaches have led to new therapies such as the use of monoclonal antibodies (mAbs) to interfere with the immune checkpoint. Others have exploited molecular technologies to re-engineer a subset of T cells to directly engage and kill tumor cells, particularly those of B cell malignancies. However, before immunotherapy can become a more effective method of cancer care, there are many challenges that remain to be addressed and hurdles to overcome. Included are manipulation of tumor microenvironment (TME) to enhance T effector cell infiltration and access to the tumor, augmentation of tumor MHC expression for adequate presentation of tumor associated antigens, regulation of cytokines and their potential adverse effects, and reduced risk of secondary malignancies as a consequence of mutations generated by the various forms of genetic engineering of immune cells. Despite these challenges, the future of immunotherapy as a standard anti-cancer therapy is encouraging.

Kras and Tumor Immunity: Friend or Foe?

“…Given the significant role of immunosuppression in promoting growth of Ras-mutant tumors, immunotherapy is an attractive therapeutic approach. Immunotherapy uses strategies aimed at activating an antitumor immune response, predominantly mediated through CD8 + cytotoxic T cells, in addition to NK cells and macrophages with tumoricidal activity (Stambrook et al 2017). These strategies can either be aimed directly at the CD8 + Tc cells or indirectly lead to their activation by inhibiting the immunosuppressive cells and factors in the TME.…”

Missed Druggable Cancer Hallmark: Cancer–Stroma Symbiotic Crosstalk as Paradigm and Hypothesis for Cancer Therapy

“…Expression of PD‐L1 is observed in a number of solid tumor types, including melanoma, bladder cancer, non‐small cell lung, head, and neck cancer, and metastatic osteosarcoma. Similarly to PD‐1, PD‐L1 is a therapeutic target, although the mechanism of PD‐1—mediated inhibition of the T cell function remains poorly understood …”

Immunotherapy of cancer is a part of biotherapy

“…Investigation into targeting the tumor microenvironment is also becoming one of the major cancer biotherapeutic strategies in the recent years [41,42] . The tumor microenvironment includes infiltration of carcinoma-associated fibroblasts such as myofibroblasts and mesenchymal stem cells, infiltration of inflammatory cells such as T cells, macrophages, DC cells, NK cells, myeloid derived suppressor cells, regulatory T cells, and infiltration of blood cells such as blood endothelial cells and lymphatic endothelail cells, and non-cellular components for remodeling of extracellular matrix, etc.…”

“…Consequently, the interference with any element of the tumor microenvironment provides an opportunity to tip off the balance of the ecosystem or counteract the cancer progression. The use of an inhibitor of checkpoint molecules, namely humanized mAb anti-CTLA-4 or anti-PD1 [43,44] , or CAR-T cells [42] in combination with chemotherapy leading to some encouraging clinical results may therefore be considered as the successful stories of targeting the tumor microenvironment.…”