Immunosuppressive Signaling Pathways as Targeted Cancer Therapies

Abstract

Immune response has been shown to play an important role in defining patient prognosis and response to cancer treatment. Tumor-induced immunosuppression encouraged the recent development of new chemotherapeutic agents that assists in the augmentation of immune responses. Molecular mechanisms that tumors use to evade immunosurveillance are attributed to their ability to alter antigen processing/presentation pathways and the tumor microenvironment. Cancer cells take advantage of normal molecular and immunoregulatory machinery to survive and thrive. Cancer cells constantly adjust their genetic makeup using several mechanisms such as nucleotide excision repair as well as microsatellite and chromosomal instability, thus giving rise to new variants with reduced immunogenicity and the ability to continue to grow without restrictions. This review will focus on the central molecular signaling pathways involved in immunosuppressive cells and briefly discuss how cancer cells evade immunosurveillance by manipulating antigen processing cells and related proteins. Secondly, the review will discuss how these pathways can be utilized for the implementation of precision medicine and deciphering drug resistance.

Direct Immunoactivation by Chemotherapeutic Drugs in Cancer Treatment

“…High-dose chemotherapeutics can exhibit cytotoxic effects on T lymphocytes, leading to prolonged immunosuppression. [110,111] In contrast, several recent studies demonstrated that chemotherapeutic agents displayed positive effects on T cells and improved T cell-mediated immune responses. [112] For example, Tseng et al found that tumor-bearing mice treated with cisplatin followed by CRT/E7 (calreticulin linked to human papillomavirus type 16 E7 antigen) DNA vaccine exhibited an increased E7-specific CD8 + T cell response, leading to effective antitumor response and longterm survival.…”

“…High‐dose chemotherapeutics can exhibit cytotoxic effects on T lymphocytes, leading to prolonged immunosuppression. [ 110,111 ] In contrast, several recent studies demonstrated that chemotherapeutic agents displayed positive effects on T cells and improved T cell‐mediated immune responses. [ 112 ] For example, Tseng et al.…”

Drug resistance mechanisms in cancers: Execution of pro-survival strategies

“…4 is one of the highly intricate processes via which cancer cells develop ways to avoid detection and destruction by the immune system, making some cancer treatments less effective. Multiple mechanisms have been demonstrated by which cancer cells avoid immune destruction including: (a) downregulation of antigen presentation [ 120 ] , (b) loss of tumor antigens [ 121 ] , (c) immune checkpoint activation [ 122 ] , (d) tumor microenvironment [ 122 ] , (e) epigenetic changes [ 123 ] , (f) tumor heterogeneity [ 124 ] , (g) influence of microbiome [ 125 ] , (h) immune escape variants; (i) immunosuppressive pathways [ 126 ] , and (j) treatment-induced changes [ 122 ] . However, discussing the details of all these mechanisms is beyond the scope of this review, and readers are directed to excellent reviews by Kim and Cho [ 122 ] and Dutta et al [ 127 ] .…”

Research progress of physical transdermal enhancement techniques in tumor therapy

“…Programmed PD1/PDL1 interactions between tumor cells and antigen-presenting cells (APCs) are also important factors contributing to the evasion of immune responses by tumor cells. 211 As a solution, immune checkpoint blockade has been proposed. For example, Gu's group designed a tumor immune recovery strategy by combining PTET in HA MNs with pH responsive dextran NPs co-loaded with GOx, CAT and aPD-1.…”